Novel compounds and compositions and methods of use

ABSTRACT

Described herein are compounds useful in the modulation of blood uric acid levels, formulations containing them and methods of using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant levels of uric acid.

RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.60/990,574, entitled “NOVEL COMPOSITIONS AND METHODS OF USING THEM”filed on Nov. 27, 2007, and U.S. Provisional Application No. 61/094,388,entitled “COMPOUNDS, COMPOSITIONS, AND METHODS OF USING SAME” filed onSep. 4, 2008, which are herein incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

Uric acid is the result of the oxidation of xanthine. Disorders of uricacid metabolism include, but are not limited to, polycythemia, myeloidmetaplasia, gout, a recurrent gout attack, gouty arthritis,hyperuricemia, hypertension, a cardiovascular disease, coronary heartdisease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidneydisease, kidney stones, kidney failure, joint inflammation, arthritis,urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.

SUMMARY OF THE INVENTION

This invention provides for methods of decreasing uric acid levels inone or more tissues or organs, blood, serum, urine, or combinationsthereof, of an individual in need of decreased uric acid levels,comprising administering to the individual a uric acid level decreasingamount of a compound of formula (I), formula (II), or formula (III) or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

This invention also provides for methods of reducing uric acidproduction, increasing uric acid excretion or both in an individual,comprising administering to the individual a compound of formula (I),formula (II), or formula (III) or a metabolite, pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

This invention also provides for methods of treating an individualsuffering from a condition characterized by abnormal tissue levels ofuric acid comprising administering to the individual an effective amountof a compound of formula (I), formula (II), or formula (III) or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof. In some embodiments, the condition ischaracterized by low tissue levels of uric acid. In further oradditional embodiments, the condition is characterized by high tissuelevels of uric acid. In further or additional embodiments, the disorderis characterized by overproduction of uric acid, low excretion of uricacid, tumor lysis, a blood disorder or a combination thereof. In furtheror additional embodiments, the blood disorder is polycythemia or myeloidmetaplasia. In further or additional embodiments, the individual in needof decreased serum uric acid levels is suffering from gout, a recurrentgout attack, gouty arthritis, hyperuricemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosis. In some preferredembodiments, the condition is gout. In some embodiments, the conditionis joint inflammation caused by deposits of uric acid crystals in thejoint. In further or additional embodiments, the uric acid crystals aredeposited in the joint fluid (synovial fluid) or joint lining (synoviallining).

This invention also provides for methods of treating or preventinghyperuricemia in an individual comprising administering to theindividual an effective amount of a compound of formula (I), formula(II), or formula (III), or a metabolite, pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof, whereinsaid amount is effective in lowering the level of uric acid.

This invention also provides for methods of treating or preventing acondition characterized by abnormal tissue levels of uric acid in anindividual at increased risk of developing the condition, comprisingadministering to the individual an effective amount of a compound offormula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof. In further or additional embodiments, the condition ispolycythemia, myeloid metaplasia, gout, a recurrent gout attack, goutyarthritis, hyperuricemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis. In some preferred embodiments, the conditionis gout. In some embodiments, the condition is joint inflammation causedby deposits of uric acid crystals in the joint. In further or additionalembodiments, the uric acid crystals are deposited in the joint fluid(synovial fluid) or joint lining (synovial lining).

This invention also provides for methods treating or preventing ofpolycythemia, myeloid metaplasia, gout, a recurrent gout attack, goutyarthritis, hyperuricemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis in an individual comprising administering tothe individual an effective amount of a compound of formula (I), formula(II), or formula (III) or a metabolite, pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof. Inpreferred embodiments, the invention provides for methods of treatinggout comprising administering to the individual an effective amount of acompound of formula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

This invention also provides for methods of preventing the formation orreducing the size of tophi/tophus in an individual, comprisingadministering to the individual an effective amount of a compound offormula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

This invention also provides for methods of decreasing uric acid levelsin one or more tissues or organs, blood, serum, urine, or combinationsthereof of an individual comprising administering to the individual auric acid level decreasing amount of a compound of formula (I), formula(II), or formula (III) or a metabolite, pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof; whereinthe reduction in uric acid levels results in a reduction in hypertensionor cardiovascular events.

This invention also provides for methods of treatinghypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in anindividual comprising administering to the individual a compound offormula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

In some embodiments, the methods described above further compriseadministering a second agent effective for the treatment of thecondition. In further or additional embodiments, the second agent iseffective in reducing tissue levels of uric acid. In further oradditional embodiments, the second agent is a nonsteroidalanti-inflammatory drug (NSAIDs), colchicine, a corticosteroid,adrenocorticotropic hormone (ACTH), probenecid, sulfinpyrazone,allopurinol, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), orcombinations thereof.

In some embodiments, the methods described above further compriseadministering a second agent effective for the treatment of thecondition. In some embodiments, the second agent is a URAT 1 inhibitor,a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthineoxidoreductase inhibitor, or combinations thereof. In further oradditional embodiments, the second agent is a nonsteroidalanti-inflammatory drug (NSAIDs), colchicine, a corticosteroid,adrenocorticotropic hormone (ACTH), probenecid, sulfinpyrazone,allopurinol, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), orcombinations thereof.

Disclosed herein, in certain embodiments, is a method of treating adisorder characterized by abnormal uric acid levels in blood and/orurine. In some embodiments, the method comprises administering (a) acompound disclosed herein; and (b) a URAT 1 inhibitor, a xanthineoxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductaseinhibitor, or combinations thereof. In some embodiments, the methodcomprises administering allopurinol, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), orcombinations thereof.

In some embodiments, the methods described herein comprise administeringa compound of formula (I). In further or additional embodiments, themethods described herein comprise administering a pharmaceuticallyacceptable salt of a compound of formula (I). In further or additionalembodiments, the methods described herein comprise administering asolvate of a compound of formula (I). In further or additionalembodiments, the methods described herein comprise administering apolymorph of a compound of formula (I). In further or additionalembodiments, the methods described herein comprise administering anester of a compound of formula (I). In further or additionalembodiments, the methods described herein comprise administering atautomer of a compound of formula (I). In further or additionalembodiments, the methods described herein comprise administering aprodrug of a compound of formula (I). In further or additionalembodiments, the methods described herein comprise administering ametabolite of a compound of formula (I). In further or additionalembodiments, the metabolite has a structure selected from:

In further or additional embodiments, the metabolite has a structureselected from:

In some embodiments, the methods described herein comprise administeringa compound of formula (II). In further or additional embodiments, themethods described herein comprise administering a pharmaceuticallyacceptable salt of a compound of formula (II). In further or additionalembodiments, the methods described herein comprise administering asolvate of a compound of formula (II). In further or additionalembodiments, the methods described herein comprise administering apolymorph of a compound of formula (II). In further or additionalembodiments, the methods described herein comprise administering anester of a compound of formula (II). In further or additionalembodiments, the methods described herein comprise administering atautomer of a compound of formula (II). In further or additionalembodiments, the methods described herein comprise administering aprodrug of a compound of formula (II). In further or additionalembodiments, the methods described herein comprise administering ametabolite of a compound of formula (II).

In some embodiments, the methods described herein comprise administeringa compound of formula (III). In further or additional embodiments, themethods described herein comprise administering a pharmaceuticallyacceptable salt of a compound of formula (III). In further or additionalembodiments, the methods described herein comprise administering asolvate of a compound of formula (III). In further or additionalembodiments, the methods described herein comprise administering apolymorph of a compound of formula (III). In further or additionalembodiments, the methods described herein comprise administering anester of a compound of formula (III). In further or additionalembodiments, the methods described herein comprise administering atautomer of a compound of formula (III). In further or additionalembodiments, the methods described herein comprise administering aprodrug of a compound of formula (III). In further or additionalembodiments, the methods described herein comprise administering ametabolite of a compound of formula (III).

In some embodiments, the individual is a mammal. In further oradditional embodiments, the mammal is a human. In some embodiments, theindividual has a disorder characterized by an abnormally high content ofuric acid in the body of the individual. In further or additionalembodiments, the disorder is characterized by overproduction of uricacid, low excretion of uric acid, tumor lysis or a blood disorder. Infurther or additional embodiments, the blood disorder is polycythemia ormyeloid metaplasia. In further or additional embodiments, the individualin need of decreased serum uric acid levels is suffering from gout, arecurrent gout attack, gouty arthritis, hyperuricemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosis.

In further or additional embodiments, the uric acid levels are decreasedby at least about 5%. In further or additional embodiments, the uricacid levels are decreased by at least about 10%. In further oradditional embodiments, the uric acid levels are decreased by at leastabout 15%. In further or additional embodiments, the uric acid levelsare decreased by at least about 20%. In further or additionalembodiments, the uric acid levels are decreased by at least about 15%.In further or additional embodiments, the uric acid levels are decreasedby at least about 30%. In further or additional embodiments, the uricacid levels are decreased by at least about 40%. In further oradditional embodiments, the uric acid levels are decreased by at leastabout 50%. In further or additional embodiments, the uric acid levelsare decreased by at least about 60%. In further or additionalembodiments, the uric acid levels are decreased by at least about 75%.In further or additional embodiments, the blood uric acid level isdecreased by at least about 0.5 mg/dL. In further or additionalembodiments, the blood uric acid level is decreased by at least about 1mg/dL. In further or additional embodiments, the blood uric acid levelis decreased by at least about 1.5 mg/dL. In further or additionalembodiments, the blood uric acid level is decreased by at least about 2mg/dL. In further or additional embodiments, the blood uric acid levelis decreased by at least about 2.5 mg/dL.

In further or additional embodiments, the tissue or organ is blood,serum or plasma.

This invention is also directed to pharmaceutical compositionscomprising effective amounts of a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof. In some embodiments, the pharmaceuticalcompositions further comprise a pharmaceutically acceptable carrier. Insome embodiments, the compositions disclosed herein contain adjuvants,excipients, preservatives, agents for delaying absorption, fillers,binders, adsorbents, buffers, disintegrating agents, solubilizingagents, other carriers, other inert ingredients, or combinationsthereof. In some embodiments, the pharmaceutical composition is in aform suitable for oral administration. In further or additionalembodiments, the pharmaceutical composition is in the form of a tablet,capsule, pill, powder, sustained release formulation, solution,suspension, for parenteral injection as a sterile solution, suspensionor emulsion, for topical administration as an ointment or cream or forrectal administration as a suppository. In further or additionalembodiments, the pharmaceutical composition is in unit dosage formssuitable for single administration of precise dosages. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.001 to about 1000 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.5 to about 50 mg/kg/day. In further or additionalembodiments the amount of compound of formula I is about 0.001 to about7 g/day. In further or additional embodiments the amount of compound offormula I is about 0.002 to about 6 g/day. In further or additionalembodiments the amount of compound of formula I is about 0.005 to about5 g/day. In further or additional embodiments the amount of compound offormula I is about 0.01 to about 5 g/day. In further or additionalembodiments the amount of compound of formula I is about 0.02 to about 5g/day. In further or additional embodiments the amount of compound offormula I is about 0.05 to about 2.5 g/day. In further or additionalembodiments the amount of compound of formula I is about 0.1 to about 1g/day. In further or additional embodiments, dosage levels below thelower limit of the aforesaid range are more than adequate. In further oradditional embodiments, dosage levels above the upper limit of theaforesaid range are required. In further or additional embodiments thecompound of formula I is administered in a single dose, once daily. Infurther or additional embodiments the compound of formula I isadministered in multiple doses, more than once per day. In further oradditional embodiments the compound of formula I is administered twicedaily. In further or additional embodiments the compound of formula I isadministered three times per day. In further or additional embodimentsthe compound of formula I is administered four times per day. In furtheror additional embodiments the compound of formula I is administered morethan four times per day. In some embodiments, the pharmaceuticalcomposition is for administration to a mammal. In further or additionalembodiments, the mammal is human. In further or additional embodiments,the pharmaceutical composition further comprises a pharmaceuticalcarrier, excipient and/or adjuvant. In further or additionalembodiments, the pharmaceutical composition further comprises at leastone therapeutic agent

In some embodiments the pharmaceutical compositions are useful fordecreasing uric acid levels. In further or additional embodiments thepharmaceutical compositions are useful for reducing hypertension orcardiovascular events.

In some embodiments, the pharmaceutical compositions comprise

i) a compound of formula (I), formula (II), or formula (III) or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof; and ii) optionally one or morepharmaceutically acceptable carriers.

In further or additional embodiments, the amount of compound of formula(I), formula (II), or formula (III) is sufficient to decrease uric acidlevels.

In further or additional embodiments, the pharmaceutical compositionscomprise:

i) a compound of formula (I), formula (II), or formula (III) or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof;

ii) a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthinedehydrogenase, a xanthine oxidoreductase inhibitor, or combinationsthereof; andiii) optionally one or more pharmaceutically acceptable carriers.

In further or additional embodiments, the pharmaceutical compositionscomprise:

i) a compound of formula (I), formula (II), or formula (III) or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof;

ii) allopurinol, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), orcombinations thereof; andiii) optionally one or more pharmaceutically acceptable carriers.

This invention also provides pharmaceutical compositions useful in thetreatment of edema and hypertension which also maintains uric acidlevels at pretreatment levels or causes a decrease in uric acid levelscomprising:

i) an antihypertensive agent;

ii) a uric acid level maintaining or lowering amount of a compound ofthe formula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof; andiii) optionally one or more pharmaceutically acceptable carriers.

This invention also provides pharmaceutical compositions useful in thetreatment of cancer which also maintains uric acid levels atpretreatment levels or causes a decrease in uric acid levels comprising:

i) an anticancer agent;

ii) a uric acid level maintaining or lowering amount of a compound ofthe formula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof; andiii) optionally one or more pharmaceutically acceptable carriers.

This invention also provides pharmaceutical compositions useful forreducing the side effects of chemotherapy in a cancer individual,comprising:

i) a uric acid level maintaining or lowering amount of a compound of theformula (I), formula (II), or formula (III) or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof; and

ii) optionally one or more pharmaceutically acceptable carriers;

wherein said side effects are related to elevated uric acid levels

In some embodiments, the pharmaceutical compositions comprise ametabolite of a compound of formula (I), formula (II), or formula (III).

In some embodiments, the metabolite has a structure selected from:

In some embodiments, the metabolite has a structure selected from:

In one aspect, provided is a compound of formula (I), or a metabolite,pharmaceutically-acceptable salt, solvate, ester, tautomer or prodrugthereof.

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^(3′) are independently selected from H and lower alkyl, or R³and R^(3′) together with the carbon to which they are attached form a4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O;

R⁴ is H, lower alkyl, lower alkenyl or lower alkynyl;

R⁵, R^(5′), R⁶, R^(6′) and R⁷ are independently selected from H, F, Cl,Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl,substituted ethyl, substituted n-propyl, substituted i-propyl,cyclopropyl, cyclobutyl, cyclopentyl, CF₃, CHF₂, CH₂F, NH₂, NHR′, NR′R″,OR′, SR′, C(O)R′, CO₂H, a salt of CO₂H, COOR′, CONH₂, CONHR′, CONR′R″,SO₃H, a salt of SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl ora heterocycle, wherein

R′ is H, C₁₋₃ alkyl, substituted C₁₋₃ alkyl wherein said substituentsare selected from CF₃, OH, OC₁₋₃ alkyl, COC₁₋₃ alkyl, COOH, COOC₁₋₃alkyl, NH₂, NHC₁₋₃ alkyl, N(C₁₋₃ alkyl)(C₁₋₃ alkyl), CONHC₁₋₃ alkyl,aryl or a heterocycle;

R″ is H, C₁₋₃ alkyl, substituted C₁₋₃ alkyl wherein said substituentsare selected from CF₃, OH, OC₁₋₃ alkyl, COC₁₋₁₃ alkyl, COOH, COOC₁₋₃alkyl, NH₂, NHC₁₋₃ alkyl, N(C₁₋₃ alkyl)(C₁₋₃ alkyl), CONHC₁₋₃ alkyl,aryl or a heterocycle; or

R′ and R″ together with the nitrogen atom to which they are attachedform a 4-, 5-, or 6-membered heterocyclic ring;

R² is selected from the group consisting of (a), (b), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′ are independently selected from N and CH;

R^(P) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃,CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ andNHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl,cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl.

In some embodiments, X is CR^(x) or N, wherein in R^(x) is H, loweralkyl, or substituted lower alkyl.

In some embodiments, R² is (a). In further or additional embodiments, R²is (b). In further or additional embodiments, R² is (c). In further oradditional embodiments, R² is (d).

In further or additional embodiments, R^(P) is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In further or additional embodiments, R⁸, R⁹and R¹⁰ are H. In further or additional embodiments, R² is (a) and R^(P)is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In further oradditional embodiments, R² is (a), R^(P) is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl and R⁸, R⁹ and R¹⁰ are H.

In some embodiments, X is N. In further or additional embodiments, X isCH. In further or additional embodiments, X is C-lower alky. In someembodiments, W is O. In further or additional embodiments, W is S. Insome embodiments, R¹ is Cl, Br, I, methyl, ethyl, n-propyl or i-propyl.In some embodiments, R³, R^(3′) and R⁴ are H. In further or additionalembodiments, X is N; W is O or S; R¹ is Cl, Br or I and R³, R^(3′) andR⁴ are H. In some embodiments, R⁵ is Cl, Br or I. In some embodiments,R⁶ is H. In further or additional embodiments, R⁵ is Cl, Br or I and R⁶is H. In further or additional embodiments, R⁷ is CO₂H, a salt of CO₂Hor COOR′. In further or additional embodiments, R⁷ is CO₂H, a salt ofCO₂H or COOR′ and R⁶ is H. In further or additional embodiments, R⁵ isCl, Br or I, R⁷ is CO₂H, a salt of CO₂H or COOR′ and R⁶ is H. In furtheror additional embodiments, R⁵ is Cl, R⁷ is CO₂H, a salt of CO₂H and R⁶is H. In further or additional embodiments, X is N, W is O or S, R¹ isCl, Br or I, R³ is H, R⁴ is H, R⁵ is Cl, Br or I, R⁶ is H and R⁷ isCO₂H, a salt of CO₂H or COOR′.

In some embodiments, the compound of formula (I) is4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof:

In some embodiments, the compound of formula (I) is a metabolite of4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid.

In further or additional embodiments the metabolite has a structureselected from:

In one aspect, provided is a compound of formula (III), or a metabolite,pharmaceutically acceptable salt, solvate, ester, tautomer or prodrugthereof:

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^(3′) are independently selected from H and lower alkyl, or R³and R^(3′) together with the carbon to which they are attached form a4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O;

R² is selected from the group consisting of (a), (b), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′ are independently selected from N and CH;

R^(P) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃,CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ andNHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl,cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl.

In some embodiments, X is N. In other embodiments, W is S or O.

In one aspect, R² is (a)

In one aspect,

represents a carbon-carbon double bond. In some embodiments, R^(P) iscyclopropyl.

In some embodiments, X is N; W is S; and R¹ is Cl, Br, I, optionallysubstituted methyl, CF₃, CHF₂ or CH₂F.

In some embodiments, R³ and R^(3′) are not H. In one aspect, R³ andR^(3′) are H.

In some embodiments, R³ and R^(3′) together with the carbon to whichthey are attached form a 4-, 5-, or 6-membered ring, optionallycontaining 1 or 2 heteroatoms selected from N, S and O. In some otherembodiments, R³ and R^(3′) together with the carbon to which they areattached form a 4-, 5-, or 6-membered ring.

In one aspect, provided herein is a compound of formula (II), whereinthe compound of formula (II) is a3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazolewherein the substituent at the 3-position is —R^(B), or pharmaceuticallyacceptable salt, solvate, or tautomer thereof:

wherein,

R^(B) is —SCH₂C(═O)R^(1a), —SCH₂-tetrazolyl, —SCH₂C(═O)NHOH,—SCH₂C(═O)O-alkyl-OC(═O)R^(3a), SCH₂C(═O)O-alkyl-OC(═O)OR^(3a),—SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b), or —SCH₂C(Oalkyl)₃;

R^(1a) is OR^(2a), SR^(3a), NR^(4a)R^(4b), at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, or a combinationthereof, wherein

R^(2a) is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl oroptionally substituted heteroaryl; or

R^(2a) is a pharmaceutically acceptable cation; or

R^(2a) is —[C(R^(5a))(R^(5b))]_(m)R^(5c);

R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionallysubstituted heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl; or

R^(3a) is —[C(R^(5a))(R^(5b))]_(n)R^(5c);

R^(4a) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; and

R^(4b) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; or

R^(4b) is [C(R^(5a))(R^(5b))]_(n)R^(5c);

each R^(5a) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^(5b) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^(5c) is hydrogen, halogen, cyano, nitro, at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉alkyl,optionally substituted L-C₂-C₅alkenyl, optionally substituted L-C₂-C₅alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionallysubstituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionallysubstituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂;

y₁ is 0, 1, 2 or 3;

Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂,OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein

Y² and Y³ are each independently hydrogen or methyl; or

Y² and Y³ are taken together with the nitrogen to which they areattached to form a five or six membered ring that optionally contains anoxygen atom or a second nitrogen atom; and

Y⁴ is an electron pair or an oxygen atom;

-   -   m is 1, 2, 3, or 4;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

wherein when R^(2a) is -[C(R^(5a))(R^(5b))]_(m)R^(5c) then at least oneof R^(5a), R^(5b) and R^(5c) is not hydrogen.

In some embodiments, R^(1a) is at least one amino acid. In someembodiments, R^(1a) is a peptide. In some embodiments, R^(1a) is alipid. In some embodiments, R^(1a) is a phospholipid. In someembodiments, R^(1a) is a glycoside. In some embodiments, R^(1a) is anucleoside. In some embodiments, R^(1a) is a nucleotide. In someembodiments, R^(1a) is polyethylene glycol.

In some embodiments, R^(1a) is a combination of one or more groupsselected from at least one amino acid, a peptide, a lipid, aphospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide,and polyethylene glycol. In some embodiments, the one or more R^(1a)groups are covalently linked. In some embodiments, the one or moreR^(1a) groups form a conjugate.

In some embodiments, R^(1a) is OR^(2a).

In some embodiments, R^(2a) is substituted C₁-C₄ alkyl or optionallysubstituted C₅-C₁₀ alkyl. In some embodiments, R^(2a) is apharmaceutically acceptable cation. In some embodiments, R^(2a) is apharmaceutically acceptable cation selected from L⁺, Na⁺, K⁺, Mg⁺⁺, Ca⁺⁺and a protonated amine.

In some embodiments, R^(2a) is [C(R^(5a))(R^(5b))]_(m)R^(5c); m is 1, 2,3, 4; and wherein at least one of R^(5a), R^(5b) and R^(5c) is nothydrogen. In some embodiments, R^(5a) is hydrogen, R^(5b) is hydrogenand R^(5c) is not hydrogen.

In some embodiments, R^(5c) is at least one amino acid, a peptide, alipid, a phospholipid, a glycoside, a nucleoside, a nucleotide,oligonucleotide, or polyethylene glycol.

In some embodiments, R^(1a) is SR^(3a). In some embodiments, R^(3a) isoptionally substituted C₁-C₁₀ alkyl.

In some embodiments, R^(3a) is —[C(R^(5a))(R^(5b))]_(n)R^(5c).

In some embodiments, R^(5a) is hydrogen, R^(5b) is hydrogen and R^(5c)is not hydrogen. In some embodiments, R^(5c) is at least one amino acid,a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, or polyethylene glycol.

In some embodiments, R^(1a) is NR^(4a)R^(4b).

In some embodiments, R^(4a) is hydrogen. In some embodiments, R^(4b) isoptionally substituted alkyl.

In some embodiments, R^(4b) is [C(R^(5a))(R^(5b))]_(n)R^(5c).

In some embodiments, R^(5a) is hydrogen, R^(5b) is hydrogen and R^(5c)is not hydrogen. In some embodiments, R^(5c) is at least one amino acid,a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, or polyethylene glycol.

In some embodiments, R^(B) is —SCH₂C(═O)R^(1a), —SCH₂-tetrazolyl,—SCH₂C(═O)NHOH, —SCH₂C(═O)O-alkyl-OC(═O)R^(3a),—SCH₂C(═O)O-alkyl-OC(═O)OR^(3a), —SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b),or —SCH₂C(Oalkyl)₃;

R^(1a) is OR^(2a), NR^(4a)R^(4b), at least one amino acid, a peptide, ora glycoside;

R^(2a) is substituted C₁-C₄ alkyl optionally substituted C₅-C₁₀ alkyloptionally substituted heteroalkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl oroptionally substituted heteroaryl; or

R^(2a) is a pharmaceutically acceptable cation;

R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionallysubstituted heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl;

R^(4a) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; and

R^(4b) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl.

In some embodiments, R^(B) is —SCH₂C(═O)R^(1a). In some embodiments,R^(B) is —SCH₂C(═O)—at least one amino acid. In some embodiments, R^(B)is —SCH₂C(═O)-lysine. In some embodiments, R^(B) is—SCH₂C(═O)-glycoside. In some embodiments, R^(B) is—SCH₂C(═O)O-glucuronide. In some embodiments, R^(B) is —SCH₂-tetrazolyl.In some embodiments, R^(B) is —SCH₂C(═O)NHOH. In some embodiments, R^(B)is —SCH₂C(═O)O-alkyl-OC(═O)R^(3a). In some embodiments,—SCH₂C(═O)O—CH₂—OC(═O)R^(3a). In some embodiments, R^(B) is—SCH₂C(═O)O—CH(CH₃)—OC(═O)R^(3a). In some embodiments, R^(B) is—SCH₂C(═O)O—CH₂—OC(═O)OR^(3a). In some embodiments, R^(B) is—SCH₂C(═O)O—CH(CH₃)—OC(═O)OR^(3a). In one aspect, R^(B) is—SCH₂C(Oalkyl)₃.

In one aspect, R^(1a) is OR^(2a). In other aspect, R^(1a) isNR^(4a)R^(4b).

In one aspect, provided is a method for decreasing uric acid levels inone or more tissues or organs, blood, serum, urine, or combinationsthereof of an individual in need of decreased uric acid levels,comprising administering to the individual a uric acid level decreasingamount of:

(i) a compound of formula (I); or

(ii) a compound of formula (II); or

(iii) a compound of formula (III); or

(iv) a combination thereof.

In one aspect, the reduction in uric acid levels results in a reductionin hypertension or cardiovascular events.

In one aspect, the method comprises administering one or moremetabolites of a compound of formula (I).

In one aspect, the compound of formula (I) is4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid or a metabolite, pharmaceutically acceptable salt, solvate, ester,tautomer or prodrug thereof.

In one aspect, the compound of formula (III) is2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid or a metabolite, pharmaceutically acceptable salt, solvate, ester,tautomer or prodrug thereof.

In some embodiments, the method comprises administering a compound offormula (III), or a metabolite, pharmaceutically acceptable salt,solvate, ester, tautomer or prodrug thereof, to the individual.

In some embodiments, the method comprises administering a compound offormula (II), wherein the compound of formula (II) is a3,5-disubstituted-4-(4-R^(C)-naphthalen-1-yl)-4H-1,2,4-triazole whereinthe substituent at the 3-position is —R^(B) and the substituent at the5-position is —R^(A), or a metabolite, pharmaceutically acceptable salt,solvate, ester, tautomer or prodrug thereof, to the individual.

In some embodiments, the method comprises administering a compound offormula (II), wherein the compound of formula (II) is a3-substituted-4-(4-cyclopropyl-naphthalen-1-yl)-4H-1,2,4-triazolewherein the substituent at the 3-position is —R^(B), or a metabolite,pharmaceutically acceptable salt, solvate, ester, tautomer or prodrugthereof, to the individual.

In some embodiments, the method comprises administering a compound offormula (I), or a metabolite, pharmaceutically acceptable salt, solvate,ester, tautomer or prodrug thereof to the individual.

In one aspect, provided is a method of treating or preventing acondition characterized by abnormal tissue or organ levels of uric acidin an individual comprising administering to the individual an effectiveamount of:

(i) a compound of formula (I); or

(ii) a compound of formula (II); or

(iii) a compound of formula (III); or

(iv) a combination thereof.

In some embodiments, the condition is gout, a recurrent gout attack,gouty arthritis, hyperuricemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase(HPRT) deficiency or a combination thereof.

In one aspect, the condition is gout. In some embodiments, the methodfurther comprises administering an additional agent effective for thetreatment of the gout. In some embodiments, the additional agent isallopurinol, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), orcombinations thereof.

In one aspect, provided is a method of treating or preventing cancerwhich also maintains uric acid levels at pretreatment levels or causes adecrease in uric acid levels, comprising administering:

a) an effective amount of an anticancer agent;

b) a uric acid level maintaining or lowering amount of

(i) a compound of formula (I); or

(ii) a compound of formula (II); or

(iii) a compound of formula (III); or

(iv) a combination thereof.

In one aspect, provided is a pharmaceutical composition comprising:

(i) a compound of formula (I); or

(ii) a compound of formula (II); or

(iii) a compound of formula (III); or

(iv) a combination of (i), (ii), and (iii); and

(v) optionally one or more pharmaceutically acceptable carriers.

In some embodiments, the pharmaceutical composition further comprisesallopurinol, febuxostat, FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), orcombinations thereof.

Throughout the specification, groups and substituents thereof are chosenby one skilled in the field to provide stable moieties and compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 represents serum uric acid (mg/dL) levels 0, 3, 7 and 14 daysafter administering4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt in humans at doses of 300 mg, 400 mg or 500 mgb.i.d. (twice daily)

FIG. 2 represents serum uric acid (μmol/L) levels 0, 3, 7 and 14 daysafter administering4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt in humans at doses of 300 mg, 400 mg or 500 mgb.i.d. (twice daily)

FIG. 3 represents the change in serum uric acid (mg/dL) levels 3, 7 and14 days after administering4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt in humans at doses of 300 mg, 400 mg or 500 mgb.i.d.

FIG. 4 represents change in serum uric acid (μmol/L) levels 3, 7 and 14days after administering4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt in humans at doses of 300 mg, 400 mg or 500 mgb.i.d.

FIG. 5 represents change in serum uric acid (μmol/dL) levels bytreatment day after administering4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt in humans at doses of 300 mg, 400 mg or 500 mgb.i.d.

FIG. 6 represents the increase in daily uric acid output following oraladministration of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid solution.

DETAILED DESCRIPTION OF THE INVENTION

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Certain Chemical Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereis a plurality of definitions for terms herein, those in this sectionprevail.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. It should alsobe noted that use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes”, and “included” is not limiting.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, IR andUV/Vis spectroscopy and pharmacology, within the skill of the art areemployed. Unless specific definitions are provided, the nomenclatureemployed herein are the standard definitions. Standard techniques can beused for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of individuals.Reactions and purification techniques can be performed e.g., using kitsof manufacturer's specifications or as commonly accomplished in the artor as described herein. The foregoing techniques and procedures can begenerally performed of conventional methods well known in the art and asdescribed in various general and more specific references that are citedand discussed throughout the present specification. Throughout thespecification, groups and substituents thereof can be chosen by oneskilled in the field to provide stable moieties and compounds.

Where substituent groups are specified by their conventional chemicalformulas, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left. As a non-limiting example, —CH₂O— isequivalent to —OCH₂—.

Unless otherwise noted, the use of general chemical terms, such asthough not limited to “alkyl,” “amine,” “aryl,” are equivalent to theiroptionally substituted forms. For example, “alkyl,” as used herein,includes optionally substituted alkyl.

In some embodiments, the compounds presented herein possess one or morestereocenters. In some embodiments, the stereocenter is in the Rconfiguration, the S configuration, or combinations thereof. In someembodiments, the compounds presented herein possess one or more doublebonds. In some embodiments, the compounds presented herein possess oneor more double bonds wherein each double bond exists in the E (trans) orZ (cis) configuration, or combinations thereof. Presentation of oneparticular stereoisomer, regioisomer, diastereomer, enantiomer or epimershould be understood to include all possible stereoisomers,regioisomers, diastereomers, enantiomers or epimers and mixturesthereof. Thus, the compounds presented herein include all separateconfigurational stereoisomeric, regioisomeric, diastereomeric,enantiomeric, and epimeric forms as well as the corresponding mixturesthereof. Techniques for inverting or leaving unchanged a particularstereocenter, and those for resolving mixtures of stereoisomers arefound, for example, Furniss et al. (eds.), VOGEL'S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific andTechnical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990,23, 128.

The terms “moiety”, “chemical moiety”, “group” and “chemical group”, asused herein refer to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “reactant,” as used herein, refers to a nucleophile orelectrophile used to create covalent linkages.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined below.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons (except in those instances where macromolecular substituents areclearly intended, e.g., polypeptides, polysaccharides, polyethyleneglycols, DNA, RNA and the like).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as theranges C₁-C₂ and C₁-C₃. Thus, by way of example only, “C₁-C₄ alkyl”indicates that there are one to four carbon atoms in the alkyl group,i.e., the alkyl group is selected from among methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means that thegroup may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9carbon atoms, or 10 carbon atoms.

The term “lower” as used herein in combination with terms such as alkyl,alkenyl or alkynyl, (i.e. “lower alkyl”, “lower alkenyl” or “loweralkynyl”) refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about six carbon atoms, more preferably one to threecarbon atoms. Examples include, but are not limited to methyl, ethyl,n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl.

The term “hydrocarbon” as used herein, alone or in combination, refersto a compound or chemical group containing only carbon and hydrogenatoms.

The terms “heteroatom” or “hetero” as used herein, alone or incombination, refer to an atom other than carbon or hydrogen. Heteroatomsare may be independently selected from among oxygen, nitrogen, sulfur,phosphorous, silicon, selenium and tin but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can be the same as each another, or some or allof the two or more heteroatoms can each be different from the others.

The term “alkyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain saturated hydrocarbon monoradical having from one toabout ten carbon atoms, more preferably one to six carbon atoms.Examples include, but are not limited to methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated.

The term “alkylene” as used herein, alone or in combination, refers to adiradical derived from the above-defined monoradical, alkyl. Examplesinclude, but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), isopropylene (—CH(CH₃)═CH₂—) and the like.

The term “alkenyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbondouble-bonds and having from two to about ten carbon atoms, morepreferably two to about six carbon atoms. The group may be in either thecis or trans conformation about the double bond(s), and should beunderstood to include both isomers. Examples include, but are notlimited to ethenyl (—CH═CH₂), 1-propenyl (—CH₂CH═CH₂),isopropenyl[C(CH₃)═CH₂], butenyl, 1,3-butadienyl and the like. Wheneverit appears herein, a numerical range such as “C₂-C₆ alkenyl” or “C₂₋₆alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, althoughthe present definition also covers the occurrence of the term “alkenyl”where no numerical range is designated.

The term “alkenylene” as used herein, alone or in combination, refers toa diradical derived from the above-defined monoradical alkenyl. Examplesinclude, but are not limited to ethenylene (—CH═CH—), the propenyleneisomers (e.g., —CH₂CH═CH— and —C(CH₃)═CH—) and the like.

The term “alkynyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbontriple-bonds and having from two to about ten carbon atoms, morepreferably from two to about six carbon atoms. Examples include, but arenot limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadienyl and thelike. Whenever it appears herein, a numerical range such as “C₂-C₆alkynyl” or “C₂₋₆ alkynyl”, means that the alkynyl group may consist of2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6carbon atoms, although the present definition also covers the occurrenceof the term “alkynyl” where no numerical range is designated.

The term “alkynylene” as used herein, alone or in combination, refers toa diradical derived from the above-defined monoradical, alkynyl.Examples include, but are not limited to ethynylene (—C≡C—),propargylene (—CH₂—C≡C—) and the like.

The term “aliphatic” as used herein, alone or in combination, refers toan optionally substituted, straight-chain or branched-chain, non-cyclic,saturated, partially unsaturated, or fully unsaturated nonaromatichydrocarbon. Thus, the term collectively includes alkyl, alkenyl andalkynyl groups.

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” as usedherein, alone or in combination, refer to optionally substituted alkyl,alkenyl and alkynyl structures respectively, as described above, inwhich one or more of the skeletal chain carbon atoms (and any associatedhydrogen atoms, as appropriate) are each independently replaced with aheteroatom (i.e. an atom other than carbon, such as though not limitedto oxygen, nitrogen, sulfur, silicon, phosphorous, tin or combinationsthereof), or heteroatomic group such as though not limited to —O—O—,—S—S—, —O—S—, —S—O—, ═N—N═, —N═N—, —N═N—NH—, —P(O)₂—, —O—P(O)₂—,—P(O)₂—O—, —S(O)—, —S(O)₂—, —SnH₂— and the like.

The terms “haloalkyl”, “haloalkenyl” and “haloalkynyl” as used herein,alone or in combination, refer to optionally substituted alkyl, alkenyland alkynyl groups respectively, as defined above, in which one or morehydrogen atoms is replaced by fluorine, chlorine, bromine or iodineatoms, or combinations thereof. In some embodiments two or more hydrogenatoms may be replaced with halogen atoms that are the same as eachanother (e.g. difluoromethyl); in other embodiments two or more hydrogenatoms may be replaced with halogen atoms that are not all the same aseach other (e.g. 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examplesof haloalkyl groups are fluoromethyl and bromoethyl. A non-limitingexample of a haloalkenyl group is bromoethynyl. A non-limiting exampleof a haloalkynyl group is chloroethynyl.

The term “perhalo” as used herein, alone or in combination, refers togroups in which all of the hydrogen atoms are replaced by fluorines,chlorines, bromines, iodines, or combinations thereof. Thus, as anon-limiting example, the term “perhaloalkyl” refers to an alkyl group,as defined herein, in which all of the H atoms have been replaced byfluorines, chlorines, bromines or iodines, or combinations thereof. Anon-limiting example of a perhaloalkyl group is bromo, chloro,fluoromethyl. A non-limiting example of a perhaloalkenyl group istrichloroethenyl. A non-limiting example of a perhaloalkynyl group istribromopropynyl.

The term “carbon chain” as used herein, alone or in combination, refersto any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl orheteroalkynyl group, which is linear, cyclic, or any combinationthereof. If the chain is part of a linker and that linker comprises oneor more rings as part of the core backbone, for purposes of calculatingchain length, the “chain” only includes those carbon atoms that composethe bottom or top of a given ring and not both, and where the top andbottom of the ring(s) are not equivalent in length, the shorter distanceshall be used in determining the chain length. If the chain containsheteroatoms as part of the backbone, those atoms are not calculated aspart of the carbon chain length.

The terms “cycle”, “cyclic”, “ring” and “membered ring” as used herein,alone or in combination, refer to any covalently closed structure,including alicyclic, heterocyclic, aromatic, heteroaromatic andpolycyclic fused or non-fused ring systems as described herein. Ringscan be optionally substituted. Rings can form part of a fused ringsystem. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, by way of example only,cyclohexane, pyridine, pyran and pyrimidine are six-membered rings andcyclopentane, pyrrole, tetrahydrofuran and thiophene are five-memberedrings.

The term “fused” as used herein, alone or in combination, refers tocyclic structures in which two or more rings share one or more bonds.

The term “cycloalkyl” as used herein, alone or in combination, refers toan optionally substituted, saturated, hydrocarbon monoradical ring,containing from three to about fifteen ring carbon atoms or from threeto about ten ring carbon atoms, though may include additional, non-ringcarbon atoms as substituents (e.g. methylcyclopropyl). Whenever itappears herein, a numerical range such as “C₃-C₆ cycloalkyl” or “C₃₋₆cycloalkyl”, means that the cycloalkyl group may consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., iscyclopropyl, cyclobutyl, cyclopentyl or cycloheptyl, although thepresent definition also covers the occurrence of the term “cycloalkyl”where no numerical range is designated. The term includes fused,non-fused, bridged and spiro radicals. A fused cycloalkyl may containfrom two to four fused rings where the ring of attachment is acycloalkyl ring, and the other individual rings may be alicyclic,heterocyclic, aromatic, heteroaromatic or any combination thereof.Examples include, but are not limited to cyclopropyl, cyclopentyl,cyclohexyl, decalinyl, and bicyclo[2.2.1]heptyl and adamantyl ringsystems. Illustrative examples include, but are not limited to thefollowing moieties:

and the like.

The term “cycloalkenyl” as used herein, alone or in combination, refersto an optionally substituted hydrocarbon non-aromatic, monoradical ring,having one or more carbon-carbon double-bonds and from three to abouttwenty ring carbon atoms, three to about twelve ring carbon atoms, orfrom three to about ten ring carbon atoms. The term includes fused,non-fused, bridged and spiro radicals. A fused cycloalkenyl may containfrom two to four fused rings where the ring of attachment is acycloalkenyl ring, and the other individual rings may be alicyclic,heterocyclic, aromatic, heteroaromatic or any combination thereof. Fusedring systems may be fused across a bond that is a carbon-carbon singlebond or a carbon-carbon double bond. Examples of cycloalkenyls include,but are not limited to cyclohexenyl, cyclopentadienyl andbicyclo[2.2.1]hept-2-ene ring systems. Illustrative examples include,but are not limited to the following moieties:

and the like.

The terms “alicyclyl” or “alicyclic” as used herein, alone or incombination, refer to an optionally substituted, saturated, partiallyunsaturated, or fully unsaturated nonaromatic hydrocarbon ring systemscontaining from three to about twenty ring carbon atoms, three to abouttwelve ring carbon atoms, or from three to about ten ring carbon atoms.Thus, the terms collectively include cycloalkyl and cycloalkenyl groups.

The terms “non-aromatic heterocyclyl” and “heteroalicyclyl” as usedherein, alone or in combination, refer to optionally substituted,saturated, partially unsaturated, or fully unsaturated nonaromatic ringmonoradicals containing from three to about twenty ring atoms, where oneor more of the ring atoms are an atom other than carbon, independentlyselected from among oxygen, nitrogen, sulfur, phosphorous, silicon,selenium and tin but are not limited to these atoms. In embodiments inwhich two or more heteroatoms are present in the ring, the two or moreheteroatoms can be the same as each another, or some or all of the twoor more heteroatoms can each be different from the others. The termsinclude fused, non-fused, bridged and spiro radicals. A fusednon-aromatic heterocyclic radical may contain from two to four fusedrings where the attaching ring is a non-aromatic heterocycle, and theother individual rings may be alicyclic, heterocyclic, aromatic,heteroaromatic or any combination thereof. Fused ring systems may befused across a single bond or a double bond, as well as across bondsthat are carbon-carbon, carbon-hetero atom or hetero atom-hetero atom.The terms also include radicals having from three to about twelveskeletal ring atoms, as well as those having from three to about tenskeletal ring atoms. Attachment of a non-aromatic heterocyclic subunitto its parent molecule can be via a heteroatom or a carbon atom.Likewise, additional substitution can be via a heteroatom or a carbonatom. As a non-limiting example, an imidazolidine non-aromaticheterocycle may be attached to a parent molecule via either of its Natoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of its carbonatoms (imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl). Incertain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples include, but are not limited topyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl and quinolizinyl. Illustrative examples of heterocycloalkylgroups, also referred to as non-aromatic heterocycles, include:

and the like.

The terms also include all ring forms of the carbohydrates, includingbut not limited to the monosaccharides, the disaccharides and theoligosaccharides.

The term “aromatic” as used herein, refers to a planar, cyclic orpolycyclic, ring moiety having a delocalized n-electron systemcontaining 4n+2 π electrons, where n is an integer. Aromatic rings canbe formed by five, six, seven, eight, nine, or more than nine atoms.Aromatics can be optionally substituted and can be monocyclic orfused-ring polycyclic. The term aromatic encompasses both all carboncontaining rings (e.g., phenyl) and those rings containing one or moreheteroatoms (e.g., pyridine).

The term “aryl” as used herein, alone or in combination, refers to anoptionally substituted aromatic hydrocarbon radical of six to abouttwenty ring carbon atoms, and includes fused and non-fused aryl rings. Afused aryl ring radical contains from two to four fused rings where thering of attachment is an aryl ring, and the other individual rings maybe alicyclic, heterocyclic, aromatic, heteroaromatic or any combinationthereof. Further, the term aryl includes fused and non-fused ringscontaining from six to about twelve ring carbon atoms, as well as thosecontaining from six to about ten ring carbon atoms. A non-limitingexample of a single ring aryl group includes phenyl; a fused ring arylgroup includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and anon-fused bi-aryl group includes biphenyl.

The term “arylene” as used herein, alone or in combination, refers to adiradical derived from the above-defined monoradical, aryl. Examplesinclude, but are not limited to 1,2-phenylene, 1,3-phenylene,1,4-phenylene, 1,2-naphthylene and the like.

The term “heteroaryl” as used herein, alone or in combination, refers tooptionally substituted aromatic monoradicals containing from about fiveto about twenty skeletal ring atoms, where one or more of the ring atomsis a heteroatom independently selected from among oxygen, nitrogen,sulfur, phosphorous, silicon, selenium and tin but not limited to theseatoms and with the proviso that the ring of said group does not containtwo adjacent O or S atoms. In embodiments in which two or moreheteroatoms are present in the ring, the two or more heteroatoms can bethe same as each another, or some or all of the two or more heteroatomscan each be different from the others. The term heteroaryl includesoptionally substituted fused and non-fused heteroaryl radicals having atleast one heteroatom. The term heteroaryl also includes fused andnon-fused heteroaryls having from five to about twelve skeletal ringatoms, as well as those having from five to about ten skeletal ringatoms. Bonding to a heteroaryl group can be via a carbon atom or aheteroatom. Thus, as a non-limiting example, an imidazole group may beattached to a parent molecule via any of its carbon atoms(imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms(imidazol-1-yl or imidazol-3-yl). Likewise, a heteroaryl group may befurther substituted via any or all of its carbon atoms, and/or any orall of its heteroatoms. A fused heteroaryl radical may contain from twoto four fused rings where the ring of attachment is a heteroaromaticring and the other individual rings may be alicyclic, heterocyclic,aromatic, heteroaromatic or any combination thereof. A non-limitingexample of a single ring heteroaryl group includes pyridyl; fused ringheteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and anon-fused bi-heteroaryl group includes bipyridinyl. Further examples ofheteroaryls include, without limitation, furanyl, thienyl, oxazolyl,acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl,benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl,indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl,pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl,purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl,quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyland the like, and their oxides, such as for example pyridyl-N-oxide.Illustrative examples of heteroaryl groups include the followingmoieties:

and the like.

The term “heteroarylene” as used herein, alone or in combination, refersto a diradical derived from the above-defined monoradical heteroaryl.Examples include, but are not limited to pyridinyl and pyrimidinyl.

The term “heterocyclyl” as used herein, alone or in combination, referscollectively to heteroalicyclyl and heteroaryl groups. Herein, wheneverthe number of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆heterocycle), at least one non-carbon atom (the heteroatom) must bepresent in the ring. Designations such as “C₁-C₆ heterocycle” refer onlyto the number of carbon atoms in the ring and do not refer to the totalnumber of atoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Forheterocycles having two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Non-aromatic heterocyclic groups includegroups having only three atoms in the ring, while aromatic heterocyclicgroups must have at least five atoms in the ring. Bonding (i.e.attachment to a parent molecule or further substitution) to aheterocycle can be via a heteroatom or a carbon atom.

The term “carbocyclyl” as used herein, alone or in combination, referscollectively to alicyclyl and aryl groups; i.e. all carbon, covalentlyclosed ring structures, which may be saturated, partially unsaturated,fully unsaturated or aromatic. Carbocyclic rings can be formed by three,four, five, six, seven, eight, nine, or more than nine carbon atoms.Carbocycles can be optionally substituted. The term distinguishescarbocyclic from heterocyclic rings in which the ring backbone containsat least one atom which is different from carbon.

The terms “halogen”, “halo” or “halide” as used herein, alone or incombination refer to fluoro, chloro, bromo and iodo.

The term “hydroxy” as used herein, alone or in combination, refers tothe monoradical —OH.

The term “cyano” as used herein, alone or in combination, refers to themonoradical —CN.

The term “cyanomethyl” as used herein, alone or in combination, refersto the monoradical —CH₂CN.

The term “nitro” as used herein, alone or in combination, refers to themonoradical —NO₂.

The term “oxy” as used herein, alone or in combination, refers to thediradical —O—.

The term “oxo” as used herein, alone or in combination, refers to thediradical ═O.

The term “carbonyl” as used herein, alone or in combination, refers tothe diradical —C(═O)—, which may also be written as —C(O)—.

The terms “carboxy” or “carboxyl” as used herein, alone or incombination, refer to the moiety —C(O)OH, which may also be written as—COOH.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, —O-alkyl, including the groups —O-aliphatic and—O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups maybe optionally substituted, and wherein the terms alkyl, aliphatic andcarbocyclyl are as defined herein. Non-limiting examples of alkoxyradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “sulfinyl” as used herein, alone or in combination, refers tothe diradical —S(═O)—.

The term “sulfonyl” as used herein, alone or in combination, refers tothe diradical —S(═O)₂—.

The terms “sulfonamide”, “sulfonamido” and “sulfonamidyl” as usedherein, alone or in combination, refer to the diradical groups—S(═O)₂—NH— and —NH—S(═O)₂—.

The terms “sulfamide”, “sulfamido” and “sulfamidyl” as used herein,alone or in combination, refer to the diradical group —NH—S(═O)₂—NH—.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

As used herein, “3,5-disubstituted4-(4-R^(C)-naphthalen-1-yl)-4H-1,2,4-triazole” refers to:

As used herein,“3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole”refers to:

The term “natural” as used herein refers to a group or compound that ispresent in or produced by nature.

The term “unnatural” or “non-natural” refers to a group or compound thatis not present in or produced by nature. An “unnatural” or “non-natural”group or compound is typically produced by human intervention. A“unnatural” or “non-natural” group or compound is artificial.

The term “amino acid” as used herein refers to a group or compound thatconsists of an amino group, a carboxyl group, a H atom and a distinctiveR group (or side chain). “Amino acid” includes, α-amino acids, β-aminoacids, δ-amino acids, and γ-amino acids. α-Amino acids consists of anamino group, a carboxyl group, a H atom and a distinctive R group whichis bonded to the α-carbon atom. “Amino acid” includes natural aminoacids, unnatural amino acids, amino acid analogs, amino acid mimics, andthe like.

In one aspect, the term “amino acid” refers to one of the naturallyoccurring twenty amino acids (i.e. α-amino acids), as shown below. Aminoacids consist of an amino group, a carboxyl group, an H atom and adistinctive R group (or side chain), all of which are bonded to anα-carbon atom. As a result of containing three differing groups on theα-carbon atom, amino acids contain a chiral center, and therefore mayexist as either of two optically active enantiomers, the D- and the L-.Naturally occurring acids are found as their L-derivatives.

In another aspect, the amino acid is an “unnatural amino acid”,“non-natural amino acid”, “amino acid analog”, “amino acid mimic”.“Unnatural amino acid”, “non-natural amino acid”, “amino acid analog”,“amino acid mimic” and the like, as used herein, refer to an amino acidthat is not one of the 20 natural amino acids. These terms refer toamino acids wherein the fundamental amino acid molecule has beenmodified in some way. Such modifications include, though are not limitedto side chain variations; substitutions on, or alterations to, theamino-CH-carboxyl backbone; D-enantiomers; combinations thereof and thelike.

These terms also include, but are not limited to, amino acids whichoccur naturally but are not naturally incorporated into a growingpolypeptide chain, such as, though not limited toN-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine,O-phosphotyrosine and the like. Further, these terms also include, butare not limited to, amino acids which do not occur naturally and may beobtained synthetically or may be obtained by modification of natural,naturally occurring or non-natural amino acids.

Illustrative examples of side chain variations include though are notlimited to, O-t-butyl-serine, hydroxyproline, 4-chlorophenylalanine,homoserine, methionine sulfoxide, thienylalanine and the like.

O-tButyl-serine Hydroxyproline 4-Chlorophenylalanine HomoserineMethionine sulfoxide 2-Thienyl alanine

Illustrative examples of backbone alterations include though are notlimited to, β-amino acids such as β-alanine, homoproline, alkylation ofthe amino group, substitution on the α-carbon atom, thiocarboxyls andthe like.

A peptide can be natural or unnatural, and consists of amino acids thatare linked together. The terms “natural peptide”, “natural polypeptide”,“natural protein” and the like, as used herein, refer to a polymer ofnatural amino acid residues linked by covalent peptide bonds, andinclude amino acid chains of any length, including full length proteins.The terms “unnatural peptide”, “peptide mimic”, “peptide analog”,“unnatural polypeptide”, “unnatural protein” and the like, as usedherein, refer to a polymer of amino acid residues of any length,including full length proteins, wherein one or more of the amino acidsis an unnatural amino acid, and/or wherein one or more of the aminoacids are joined by chemical means other than natural peptide bonds.Illustrative examples of linking groups that can be used as alternativesto the natural peptide bond include, but are not limited to ethylene(—CH₂—CH₂—), ethynylene (—CH═CH—), ketomethylene (—C(═O)CH₂— or—CH₂C(═O)—), aminomethylene (—CH₂—NH— or —NH—CH₂—), methylene ether(—CH₂—O— or —O—CH₂—), thioether (—CH₂—S— or —S—CH₂—), thioamide(—C(═S)NH— or —NH—C(═S)—), ester (—C(═O)O— or O—C(═O)—), tetrazole,thiazole and the like.

“Nucleoside” is a glycosylamine consisting of a nucleobase (oftenreferred to simply base) bound to a ribose or deoxyribose sugar. Anucleoside can be a natural nucleoside or an unnatural nucleoside. Theterm “natural nucleoside” as used herein refers to a nucleobase bound toa ribose or deoxyribose sugar. Examples of these include cytidine,uridine, adenosine, guanosine, thymidine and inosine.

The terms “unnatural nucleoside”, “nucleoside analog” and the like, asused herein, refer to a nucleoside that is not one of the 6 nucleosides.These terms refer to nucleosides wherein the fundamental nucleosidemolecule has been modified in some way. Such modifications include,though are not limited to base modifications, sugar modifications,alterations of the linkages between the base and sugar, use of alternatestereochemistries; combinations thereof and the like.

The terms “nucleotide”, “polynucleotide”, “oligonucleotide”, “nucleicacid”, “nucleic acid polymer” and the like, as used herein, refer todeoxyribonucleotides, deoxyribonucleosides, ribonucleosides orribonucleotides and polymers thereof in either single- ordouble-stranded form, including, but not limited to, (i) analogues ofnatural nucleotides which have similar binding properties as a referencenucleic acid and are metabolized in a manner similar to naturallyoccurring nucleotides; (ii) oligonucleotide analogs including, but arenot limited to, PNA (peptidonucleic acid), analogs of DNA used inantisense technology (phosphorothioates, phosphoroamidates, and thelike).

The term lipid” as used herein refers to any fat-soluble (lipophilic),naturally-occurring molecule, such as fats, oils, waxes, cholesterol,sterols, fat-soluble vitamins (such as vitamins A, D, E and K),monoglycerides, diglycerides, phospholipids, fatty acid, fatty acidesters, and the like. Lipids can be natural or unnatural. In one aspectthe lipid is a fatty acid. Fatty acids are saturated or unsaturated.Saturated fatty acids include, but are not limited to, lauric acid,myristic acid, palmitic acid, stearic acid, arachidic acid. Unsaturatedfatty acids include, but are not limited to, palmitoleic acid, oleicacid, linoleic acid, linolenic acid, arachidonic acid.

“Phospholipid” is a type of lipid that is amphipathic. Phospholipids area class of lipids and contain a glycerol backbone, where two of thehydroxy groups of the glycerol backbone are esterified with fatty acid(saturated, unsaturated, natural, unnatural), and the third hydroxy isused to form a phosphate ester with phosphoric acid. The phosphatemoiety of the resulting phosphatidic acid is further esterified withethanolamine, choline or serine. Phospholipids are either natural orunnatural. Natural phospholipids include, but are not limited to,plasmalogen, cardiolipin, dipalmitoylphosphatidylcholine,glycerophospholipid, glycerophosphoric acid, lecithin, lysophosphatidicacid, phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidylinositol (3,4)-bisphosphate,phosphatidylinositol (3,4,5)-trisphosphate, phosphatidylinositol(3,5)-bisphosphate, phosphatidylinositol (4,5)-bisphosphate,phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate,phosphatidylinositol phosphate, phosphatidylmyo-inositol mannosides,phosphatidylserine, platelet-activating factor, sphingomyelin,sphingosyl phosphatide. “Unnatural phospholipids” contain a diglyceride,a phosphate group, and a simple organic molecule such as choline but areprepared by nature.

“Glycoside” as used herein refers to a group comprising any hydrophilicsugar (e.g. sucrose, maltose, glucose, glucuronic acid, and the like). Aglycoside is any sugar group bonded through a glycosidic linkage.Glycosides include natural glycosides and unnatural glycosides.Glycosides include asymmetric carbon(s) and exist in L-form or D-form.Natural glycosides preferentially exist in the D-form. Glycosidesinclude monosaccharides, disaccharides, and polysaccharides. Examples ofmonosaccharides include, but are not limited to, trioses (e.g.glyceraldehyde, dihydroxyacetone), tetroses (e.g. erythrose, threose,erythrulose), pentoses (e.g. arabinose, lyxose, ribose, deoxyribose,xylose, ribulose, xylulose), hexoses (allose, altrose, galactose,glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose,tagatose), heptoses (mannoheptulose, sedoheptulose); octoses (e.g.octolose, 2-keto-3-deoxy-manno-octonate), nonoses (e.g. sialose).Disaccharide include, but are not limited to, sucrose, lactose, maltose,trehalose, cellobiose, kojibiose, nigerose, isomaltose, β,β-trehalose,sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose,gentiobiulose, mannobiose, melibiose, melibiulose, rutinose, rutinulose,xylobiose. Polysaccharides include glycans. Aza-sugars are also includedwithin the term “glycoside”.

The term “polyethylene glycol” refers to linear or branched polymericpolyether polyols.

Certain Pharmaceutical Terminology

The term “patient”, “subject” or “individual” are used interchangeably.As used herein, they refer to individuals suffering from a disorder, andthe like, encompasses mammals and non-mammals. None of the terms requirethat the individual be under the care and/or supervision of a medicalprofessional. Mammals are any member of the Mammalian class, includingbut not limited to humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In some embodiments of the methods andcompositions provided herein, the individual is a mammal. In preferredembodiments, the individual is a human.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition or one or more symptoms thereof, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disease or condition, e.g., arrestingthe development of the disease or condition, relieving the disease orcondition, causing regression of the disease or condition, relieving acondition caused by the disease or condition, or stopping the symptomsof the disease or condition, and are intended to include prophylaxis.The terms further include achieving a therapeutic benefit and/or aprophylactic benefit. By therapeutic benefit is meant eradication oramelioration of the underlying disorder being treated. Also, atherapeutic benefit is achieved with the eradication or amelioration ofone or more of the physiological symptoms associated with the underlyingdisorder such that an improvement is observed in the individual,notwithstanding that the individual is still be afflicted with theunderlying disorder. For prophylactic benefit, the compositions areadministered to an individual at risk of developing a particulardisease, or to an individual reporting one or more of the physiologicalsymptoms of a disease, even though a diagnosis of this disease has notbeen made.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In preferred embodiments, the compounds andcompositions described herein are administered orally.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to asufficient amount of at least one agent or compound being administeredwhich will relieve to some extent one or more of the symptoms of thedisease or condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in a disease. An appropriate “effective” amount maydiffer from one individual to another. An appropriate “effective” amountin any individual case may be determined using techniques, such as adose escalation study.

The term “acceptable” as used herein, with respect to a formulation,composition or ingredient, means having no persistent detrimental effecton the general health of the individual being treated.

The term “pharmaceutically acceptable” as used herein, refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compounds described herein, andis relatively nontoxic, i.e., the material may be administered to anindividual without causing undesirable biological effects or interactingin a deleterious manner with any of the components of the composition inwhich it is contained.

The term “prodrug” as used herein, refers to a drug precursor that,following administration to an individual and subsequent absorption, isconverted to an active, or a more active species via some process, suchas conversion by a metabolic pathway. Thus, the term encompasses anyderivative of a compound, which, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or a pharmaceutically active metabolite or residue thereof.Some prodrugs have a chemical group present on the prodrug that rendersit less active and/or confers solubility or some other property to thedrug. Once the chemical group has been cleaved and/or modified from theprodrug the active drug is generated. Prodrugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent is not. Particularly favored derivatives or prodrugsare those that increase the bioavailability of the compounds of thisinvention when such compounds are administered to an individual (e.g. byallowing an orally administered compound to be more readily absorbedinto the blood) or which enhance delivery of the parent compound to abiological compartment (e.g. the brain or lymphatic system).

The term “pharmaceutically acceptable salt” as used herein, refers tosalts that retain the biological effectiveness of the free acids andbases of the specified compound and that are not biologically orotherwise undesirable. Compounds described herein may possess acidic orbasic groups and therefore may react with any of a number of inorganicor organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. These salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound in its freebase form with a suitable organic or inorganic acid, and isolating thesalt thus formed.

The term “pharmaceutical composition,” as used herein, refers to abiologically active compound, optionally mixed with at least onepharmaceutically acceptable chemical component, such as, though notlimited to carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, excipients and the like.

The term “carrier” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “pharmaceutical combination”, “administering an additionaltherapy”, “administering an additional therapeutic agent” and the like,as used herein, refer to a pharmaceutical therapy resulting from themixing or combining of more than one active ingredient and includes bothfixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that at least one of the compounds describedherein, and at least one co-agent, are both administered to anindividual simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that at least one of the compoundsdescribed herein, and at least one co-agent, are administered to anindividual as separate entities either simultaneously, concurrently orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the individual. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

The terms “co-administration”, “administered in combination with” andtheir grammatical equivalents or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singleindividual, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the compoundsdescribed herein will be co-administered with other agents. These termsencompass administration of two or more agents to an animal so that bothagents and/or their metabolites are present in the animal at the sametime. They include simultaneous administration in separate compositions,administration at different times in separate compositions, and/oradministration in a composition in which both agents are present. Thus,in some embodiments, the compounds of the invention and the otheragent(s) are administered in a single composition. In some embodiments,compounds of the invention and the other agent(s) are admixed in thecomposition.

The term “metabolite,” as used herein, refers to a derivative of acompound which is formed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of a compound that is formed when the compound ismetabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. Thus, enzymes may produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulfhydryl groups. Further informationon metabolism may be obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996).

Compounds

Described herein are compounds of formula I, metabolites,pharmaceutically acceptable salts, solvates, polymorphs, esters,tautomers or prodrugs thereof:

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^(3′) are independently selected from H and lower alkyl, or R³and R^(3′) together with the carbon to which they are attached form a4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O;

R⁴ is H, lower alkyl, lower alkenyl or lower alkynyl;

R⁵, R^(5′), R⁶, R^(6′) and R⁷ are independently selected from H, F, Cl,Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl,substituted ethyl, substituted n-propyl, substituted i-propyl,cyclopropyl, cyclobutyl, cyclopentyl, CF₃, CHF₂, CH₂F, NH₂, NHR′, NR′R″,OR′, SR′, C(O)R′, CO₂H, a salt of CO₂H, COOR′, CONH₂, CONHR′, CONR′R″,SO₃H, a salt of SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl ora heterocycle, wherein

R′ is H, C₁₋₃ alkyl, substituted C₁₋₃ alkyl wherein said substituentsare selected from CF₃, OH, OC₁₋₃ alkyl, COC₁₋₃ alkyl, COOH, COOC₁₋₃alkyl, NH₂, NHC₁₋₃ alkyl, N(C₁₋₃ alkyl)(C₁₋₃ alkyl), CONHC₁₋₃ alkyl,aryl or a heterocycle;

R″ is H, C₁₋₃ alkyl, substituted C₁₋₃ alkyl wherein said substituentsare selected from CF₃, OH, OC₁₋₃ alkyl, COC₁₋₃ alkyl, COOH, COOC₁₋₃alkyl, NH₂, NHC₁₋₃ alkyl, N(C₁₋₃ alkyl)(C₁₋₃ alkyl), CONHC₁₋₃ alkyl,aryl or a heterocycle; or

R′ and R″ together with the nitrogen atom to which they are attachedform a 4-, 5-, or 6-membered heterocyclic ring;

R² is selected from the group consisting of (a), (b), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′ are independently selected from N and CH;

R^(P) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃,CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ andNHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl,cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl.

In some embodiments, R² is (a). In further or additional embodiments, R²is (b). In further or additional embodiments, R² is (c). In further oradditional embodiments, R² is (d).

In further or additional embodiments, R^(P) is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In further or additional embodiments, R⁸, R⁹and R¹⁰ are H. In further or additional embodiments, R² is (a) and R^(P)is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In further oradditional embodiments, R² is (a), R^(P) is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl and R⁸, R⁹ and R¹⁰ are H.

In some embodiments, X is N. In further or additional embodiments, X isCH. In further or additional embodiments, X is C-lower alky. In someembodiments, W is O. In further or additional embodiments, W is S. Insome embodiments, R¹ is Cl, Br, I, methyl, ethyl, n-propyl or i-propyl.In some embodiments, R³ and R⁴ are H. In further or additionalembodiments, X is N; W is O or S; R¹ is Cl, Br or I and R³ and R⁴ are H.In some embodiments, R⁵ is Cl, Br or I. In some embodiments, R⁶ is H. Infurther or additional embodiments, R⁵ is Cl, Br or I and R⁶ is H. Infurther or additional embodiments, R⁷ is CO₂H, a salt of CO₂H or COOR′.In further or additional embodiments, R⁷ is CO₂H, a salt of CO₂H orCOOR′ and R⁶ is H. In further or additional embodiments, R⁵ is Cl, Br orI, R⁷ is CO₂H, a salt of CO₂H or COOR′ and R⁶ is H. In further oradditional embodiments, R⁵ is Cl, R⁷ is CO₂H, a salt of CO₂H and R⁶ isH. In further or additional embodiments, X is N, W is O or S, R¹ is Cl,Br or I, R³ is H, R⁴ is H, R⁵ is Cl, Br or I, R⁶ is H and R⁷ is CO₂H, asalt of CO₂H or COOR′

In some embodiments, the compound of formula (I) is a metabolite of acompound of formula (I). In further or additional embodiments, themetabolite has a structure selected from:

In some embodiments, the compound of formula (I) is4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof:

In some embodiments, the compound of formula (I) is a metabolite of4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid.

In further or additional embodiments the metabolite has a structureselected from:

In one aspect, provided herein is a compound of formula (II), whereinthe compound of formula (II) is a3,5-disubstituted-4-(4-R^(C)-naphthalen-1-yl)-4H-1,2,4-triazole whereinthe substituent at the 3-position is —R^(B) and the substituent at the5-position is —R^(A), or pharmaceutically acceptable salt, solvate, ortautomer thereof:

wherein,

R^(A) is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl,optionally substituted methyl, optionally substituted ethyl, optionallysubstituted n-propyl, optionally substituted i-propyl, CF₃, CHF₂ orCH₂F;

R^(B) is —SCH₂C(═O)R^(1a), —SCH₂-tetrazolyl, —SCH₂C(═O)NHOH,—SCH₂C(O)O-alkyl-OC(═O)R^(3a), —SCH₂C(═O)O-alkyl-OC(═O)OR³,—SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b), or —SCH₂C(Oalkyl)₃;

R^(C) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropylmethyl;

R^(1a) is OR^(2a), SR^(3a), NR^(4a)R^(4b), at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, or a combinationthereof, wherein

R^(2a) is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl oroptionally substituted heteroaryl; or

R^(2a) is a pharmaceutically acceptable cation;

R^(2a) is -[C(R^(5a))(R^(5b))]_(m)R^(5c); or

R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionallysubstituted heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl; or

R^(3a) is —[C(R^(5a))(R^(5b))]_(n)R^(5c);

R^(4a) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; and

R^(4b) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; or

R^(4b) is [C(R^(5a))(R^(5b))]_(n)R^(5c);

each R^(5a) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^(5b) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^(5c) is hydrogen, halogen, cyano, nitro, at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl,optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionallysubstituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionallysubstituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂;

y₁ is 0, 1, 2 or 3;

Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂,OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein

Y² and Y³ are each independently hydrogen or methyl; or

Y² and Y³ are taken together with the nitrogen to which they areattached to form a five or six membered ring that optionally contains anoxygen atom or a second nitrogen atom; and

Y⁴ is an electron pair or an oxygen atom;

-   -   m is 1, 2, 3, or 4;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In some embodiments, R^(A) is Br; and R^(C) is cyclopropyl.

In one aspect, the compound of formula (II) is a3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazolewherein the substituent at the 3-position is —R^(B).

In some embodiments, R^(1a) is at least one amino acid. In someembodiments, R^(1a) is a peptide. In some embodiments, R^(1a) is alipid. In some embodiments, R^(1a) is a phospholipid. In someembodiments, R^(1a) is a glycoside. In some embodiments, R^(1a) is anucleoside. In some embodiments, R^(1a) is a nucleotide. In someembodiments, R^(1a) is polyethylene glycol.

In some embodiments, R^(1a) is a combination of one or more groupsselected from at least one amino acid, a peptide, a lipid, aphospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide,and polyethylene glycol. In some embodiments, the one or more R^(1a)groups are covalently linked. In some embodiments, the one or moreR^(1a) groups form a conjugate.

In some embodiments, R^(1a) is OR^(2a).

In some embodiments, R^(2a) is substituted C₁-C₄ alkyl or optionallysubstituted C₅-C₁₀ alkyl. In some embodiments, R^(2a) is apharmaceutically acceptable cation. In some embodiments, R^(2a) is apharmaceutically acceptable cation selected from Li⁺, Na⁺, K⁺, Mg⁺⁺,Ca⁺⁺ and a protonated amine.

In some embodiments, R^(2a) is [C(R^(5a))(R^(5b))]_(m)R^(5c); m is 1, 2,3, 4; and wherein at least one of R^(5a), R^(5b) and R^(5c) is nothydrogen. In some embodiments, R^(5a) is hydrogen, R^(5b) is hydrogenand R^(5c) is not hydrogen.

In some embodiments, R^(5c) is at least one amino acid, a peptide, alipid, a phospholipid, a glycoside, a nucleoside, a nucleotide,oligonucleotide, or polyethylene glycol.

In some embodiments, R^(1a) is SR^(3a). In some embodiments, R^(3a) isoptionally substituted C₁-C₁₀ alkyl.

In some embodiments, R^(3a) is [C(R^(5a))(R^(5b))]_(n)R^(5c).

In some embodiments, R^(5a) is hydrogen, R^(5b) is hydrogen and R^(5c)is not hydrogen. In some embodiments, R^(5c) is at least one amino acid,a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, or polyethylene glycol.

In some embodiments, R^(1a) is NR^(4a)R^(4b).

In some embodiments, R^(4a) is hydrogen. In some embodiments, R^(4b) isoptionally substituted alkyl.

In some embodiments, R^(4b) is -[C(R^(5a))(R^(5b))]_(n)R^(5c).

In some embodiments, R^(5a) is hydrogen, R^(5b) is hydrogen and R^(5c)is not hydrogen. In some embodiments, R^(5c) is at least one amino acid,a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, or polyethylene glycol.

In some embodiments, R^(B) is —SCH₂C(═O)R^(1a), —SCH₂-tetrazolyl,—SCH₂C(═O)NHOH, —SCH₂C(═O)O-alkyl-OC(═O)R^(3a),—SCH₂C(═O)O-alkyl-OC(═O)OR^(3a), —SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b),or —SCH₂C(Oalkyl)₃;

R^(1a) is OR^(2a), NR^(4a)R^(4b), at least one amino acid, a peptide, ora glycoside;

R^(2a) is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyloptionally substituted heteroalkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl oroptionally substituted heteroaryl; or

R^(2a) is a pharmaceutically acceptable cation;

R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionallysubstituted heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl;

R^(4a) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; and

R^(4b) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl.

In some embodiments, R^(B) is —SCH₂C(═O)R^(1a). In some embodiments,R^(B) is —SCH₂C(═O)—at least one amino acid. In some embodiments, R^(B)is —SCH₂C(═O)-lysine. In some embodiments, R^(B) is—SCH₂C(═O)-glycoside. In some embodiments, R^(B) is—SCH₂C(═O)O-glucuronide. In some embodiments, R^(B) is —SCH₂-tetrazolyl.In some embodiments, R^(B) is —SCH₂C(═O)NHOH. In some embodiments, R^(B)is —SCH₂C(═O)O-alkyl-OC(═O)R^(3a). In some embodiments,—SCH₂C(O)O—CH₂—OC(═O)R^(3a). In some embodiments, R^(B) is—SCH₂C(═O)O—CH(CH₃)—OC(═O)R^(3a). In some embodiments, R^(B) is—SCH₂C(═O)O—CH₂—OC(═O)OR^(3a). In some embodiments, R^(B) is—SCH₂C(═O)O—CH(CH₃)—OC(═O)OR^(3a). In one aspect, R^(B) is—SCH₂C(Oalkyl)₃.

In one aspect, R^(1a) is OR^(2a). In other aspect, R^(1a) isNR^(4a)R^(4b).

In one aspect, R^(B) is a groups selected from —SCH₂C(═O)R^(1a),—SCH₂-tetrazolyl, —SCH₂C(═O)NHOH, —SCH₂C(═O)O-alkyl-OC(═O)R³,—SCH₂C(═O)O-alkyl-OC(═O)OR^(3a), —SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b),or —SCH₂C(Oalkyl)₃ such that R^(B) is metabolized in vivo to provideR^(B) is —SCH₂C(═O)OH.

In one aspect, provided is a compound of formula (III), or a metabolite,pharmaceutically acceptable salt, solvate, ester, tautomer or prodrugthereof:

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^(3′) are independently selected from H and lower alkyl, or R³and R^(3′) together with the carbon to which they are attached form a4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O;

R² is selected from the group consisting of (a), (O)), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′ are independently selected from N and CH;

R^(P) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃,CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ andNHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl,cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl.

In some embodiments, X is N. In other embodiments, W is S or O.

In one aspect, R² is (a)

In one aspect,

represents a carbon-carbon double bond. In some embodiments, R^(P) iscyclopropyl.

In some embodiments, X is N; W is S; and R¹ is Cl, Br, I, optionallysubstituted methyl, CF₃, CHF₂ or CH₂F.

In some embodiments, R³ and R^(3′) are not H. In one aspect, R³ andR^(3′) are H.

In some embodiments, R³ and R^(3′) together with the carbon to whichthey are attached form a 4-, 5-, or 6-membered ring, optionallycontaining 1 or 2 heteroatoms selected from N, S and O. In some otherembodiments, R³ and R^(3′) together with the carbon to which they areattached form a 4-, 5-, or 6-membered ring.

In further or additional embodiments, compounds of formula (III) havethe structures below:

Synthetic Procedures

In another aspect, methods for synthesizing the compounds describedherein are provided. In some embodiments, the compounds described hereincan be prepared by the methods described below. The procedures andexamples below are intended to illustrate those methods. Neither theprocedures nor the examples should be construed as limiting theinvention in any way. In some embodiments, compounds described hereinare synthesized by any suitable method.

In some embodiments, the starting materials used for the synthesis ofthe compounds as described herein are obtained from commercial sources,such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.). In some embodiments, the starting materials used for thesynthesis of the compounds as described herein are synthesized usingtechniques and materials described, for example, in March, ADVANCEDORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCEDORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), andGreen and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed.,(Wiley 1999) (all of which are incorporated by reference for suchdisclosure). In some embodiments, the following synthetic methods areutilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. The table below entitled “Examples of Covalent Linkagesand Precursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups.

Examples of Covalent Linkages and Precursors Thereof

Covalent Linkage Product Electrophile Nucleophile Carboxamides Activatedesters Amines/anilines Carboxamides Acyl azides Amines/anilinesCarboxamides Acyl halides Amines/anilines Esters Acyl halidesAlcohols/phenols Esters Acyl nitriles Alcohols/phenols Carboxamides Acylnitriles Amines/anilines Imines Aldehydes Amines/anilines HydrazonesAldehydes or ketones Hydrazines Oximes Aldehydes or ketonesHydroxylamines Alkyl amines Alkyl halides Amines/anilines Esters Alkylhalides Carboxylic acids Thioethers Alkyl halides Thiols Ethers Alkylhalides Alcohols/phenols Thioethers Alkyl sulfonates Thiols Esters Alkylsulfonates Carboxylic acids Ethers Alkyl sulfonates Alcohols/phenolsEsters Anhydrides Alcohols/phenols Carboxamides AnhydridesAmines/anilines Thiophenols Aryl halides Thiols Aryl amines Aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides Carboxylic acids Amines/anilines Esters Carboxylic acidsAlcohols Hydrazines Hydrazides Carboxylic acids N-acylureas orAnhydrides Carbodiimides Carboxylic acids Esters Diazoalkanes Carboxylicacids Thioethers Epoxides Thiols Thioethers Haloacetamides ThiolsAmmotriazines Halotriazines Amines/anilines Triazinyl ethersHalotriazines Alcohols/phenols Amidines Imido esters Amines/anilinesUreas Isocyanates Amines/anilines Urethanes Isocyanates Alcohols/phenolsThioureas Isothiocyanates Amines/anilines Thioethers Maleimides ThiolsPhosphite esters Phosphoramidites Alcohols Silyl ethers Silyl halidesAlcohols Alkyl amines Sulfonate esters Amines/anilines ThioethersSulfonate esters Thiols Esters Sulfonate esters Carboxylic acids EthersSulfonate esters Alcohols Sulfonamides Sulfonyl halides Amines/anilinesSulfonate esters Sulfonyl halides Phenols/alcohols

Use of Protecting Groups

In some embodiments of the reactions described herein, it is necessaryto protect reactive functional groups, for example hydroxy, amino,imino, thio or carboxy groups, where these are desired in the finalproduct, to avoid their unwanted participation in the reactions.Protecting groups are used to block some or all reactive moieties andprevent such groups from participating in chemical reactions until theprotective group is removed. It is preferred that each protective groupbe removable by a different means. Protective groups that are cleavedunder totally disparate reaction conditions fulfill the requirement ofdifferential removal. Protective groups can be removed by acid, base,and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and, in some embodiments, are usedto protect carboxy and hydroxy reactive moieties in the presence ofamino groups protected with Cbz groups, which are removable byhydrogenolysis, and Fmoc groups, which are base labile. In someembodiments, carboxylic acid and hydroxy reactive moieties are blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

In some embodiments, carboxylic acid and hydroxy reactive moieties arealso blocked with hydrolytically removable protective groups such as thebenzyl group, while amine groups capable of hydrogen bonding with acidsare blocked with base labile groups such as Fmoc. In some embodiments,carboxylic acid reactive moieties are protected by conversion to simpleester compounds as exemplified herein, or they are blocked withoxidatively-removable protective groups such as 2,4-dimethoxybenzyl,while co-existing amino groups are blocked with fluoride labile silylcarbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. In some embodiments, the compoundsdisclosed herein, or intermediate forms thereof, are attached to aresin. As long as the residue is attached to the resin, that functionalgroup is blocked and cannot react. Once released from the resin, thefunctional group is available to react.

In some embodiments, protecting or blocking groups are selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

Preparing Compounds of Formula I

Described herein are processes for the preparation of compounds offormula I. In some embodiments, synthesis of the compounds of theinvention are performed following procedures substantially as describedin WO 2004/030611, WO 2004/050643, WO/2004/030611, US 2008/0176850, US2006/013556, U.S. Pat. No. 5,939,462, and U.S. Pat. No. 7,435,752

In one synthetic route, a suitably substituted (R⁵, R⁶, R⁷) aniline isamidated with an activated carboxylic acid compound (L²-CHR³—C(O)-L¹,preferably L¹ is a halide), wherein the activated carboxylic acidcompound further includes a leaving group L² (preferably bromide). Afterformation of the anilide, the reaction product is reacted with a —WHsubstituted triazole or imidazole displacing the leaving group to formthe desired compound as depicted below.

This scheme is advantageous where the triazole or imidazole is valuablerelative to the aniline, since it is not used until the last step and isnot subjected to the inevitable losses that occur during the syntheticmanipulation of intermediates. The choice of leaving groups L¹ and L²will depend to some extent on the particular choice of amine and to alesser degree on the particular triazole or imidazole. It isparticularly preferred that L¹ and L² are halide, most preferablychloride or bromide. Suitable solvents for the amidation reactioninclude ethers, alcohols, and hydrocarbons (preferably halogenated) andthe choice of suitable solvents will at least in part depend on thechemical nature of the reactants. With respect to the solvents,catalysts and/or bases employed in the above reaction, theconsiderations described by Connell et al. (U.S. Pat. No. 5,939,462)will generally apply. Reaction of the triazole/imidazole and anilideprecursors is typically carried out in a polar aprotic solvent such asDMF, in the presence of a base such as potassium carbonate. In somecases, the base is not necessary.

An example of the anilide formation reaction, using chloroacetylchloride, is shown below.

Synthetic routes for the preparation of triazole precursors, withvarious R¹ substituents (Me, CHF₂, NH₂, CH₂OMe, CF₃), are shown below.

In some embodiments, an R¹ halogen-substituted triazole is prepared bydehalogenation of a triazole, followed by displacement of one of thehalides, as shown below.

In some embodiments, an R¹ halogen-substituted triazoles is prepared bydiazotization of an aminotriazole, as shown below.

Synthetic routes for the preparation of imidazole derivatives are shownbelow.

Preparing Compounds of Formula II

The compounds described herein can be prepared via a variety ofsynthetic routes, as would be appreciated by one of skill in the art ofchemical syntheses. For illustrative purposes, examples of some of theseroutes are shown below.

Synthetic intermediate2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid can be reacted with an alcohol, a thiol, a primary or secondaryamine, in the presence of a coupling agent (such asN,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the like) toform the ester, thioester or amide derivatives.

2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid can also be converted to2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetylchloride, via treatment with thinly chloride, and then reacted with analcohol, a thiol, a primary or secondary amine to form the ester oramide derivatives.

In a slightly different approach, intermediate5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol canbe reacted with a 2-chloro-acetic acid, 2-chloroethanethioate or2-chloro-acetamide derivative to give the same ester, thioester or amidederivatives as above.

Synthetic intermediate5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol canbe reacted with an alcohol, a thiol, a primary or secondary amine, toform the corresponding ester, thioester or amide, which are thenconverted to the 5-bromo derivatives via, for example, reaction withsodium nitrite/dichloroacetic acid/N-benzyl-N,N-diethylethanaminiumbromide.

Synthetic intermediate2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid can be coupled (using standard amino acid coupling conditions) withthe amine functionality of a natural or unnatural amino acid residue(either the α-amine or the non-α-amine of an amino acid such as lysine)to form amino acid conjugates such as those shown below.

In some embodiments, synthetic intermediate2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid is coupled (using standard coupling conditions) with a hydroxygroup of a natural or unnatural glycoside to form glycoside conjugatessuch as those shown below. In some embodiments, each of the otherhydroxyl groups is protected, unprotected (i.e. —OH) or furthersubstituted.

2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid can be reacted with hydroxylamine to form2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-hydroxyacetamide.Use of an N-substituted hydroxylamine, would provide the N-substitutedproduct.

Further Forms of Compounds of the Compounds Disclosed Herein

Isomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, compounds exist astautomers. The compounds described herein include all possible tautomerswithin the formulas described herein. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration, or S configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracernization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸Fand ³⁶Cl, respectively. Compounds described herein, and the metabolites,pharmaceutically acceptable salts, esters, prodrugs, solvate, hydratesor derivatives thereof which contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of this invention.Certain isotopically-labeled compounds, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³Hand carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereofis prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Metabolites

In some embodiments, the compounds described herein exist as theirmetabolites. In some embodiments, the methods disclosed herein includemethods of treating diseases by administering such metabolites. In someembodiments, the methods disclosed herein include methods of treatingdiseases by administering such metabolites as pharmaceuticalcompositions.

The compounds described herein are metabolized by a variety of metabolicmechanisms (e.g. hydrolysis, oxidation, glycolysis, phosphorylation,alkylation, and the like). Though not wishing to be bound by anyparticular theory, the scheme below illustrates two possible cleavagesites at which a compound of formula (I) could be metabolized to producethe metabolites indicated. Those of skill in the art could envisageadditional metabolic pathways to produce other metabolites, which arealso intended to be included herein.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate. metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary or tertiary amine. Representative alkali or alkalineearth salts include the lithium, sodium, potassium, calcium, magnesium,and aluminum salts and the like. Illustrative examples of bases includesodium hydroxide, potassium hydroxide, choline hydroxide, sodiumcarbonate, N⁺(C₁₋₄ alkyl)₄, and the like.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization. The compounds described herein can be prepared aspharmaceutically acceptable salts formed when an acidic proton presentin the parent compound either is replaced by a metal ion, for example analkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base. Base addition salts can also beprepared by reacting the free acid form of the compounds describedherein with a pharmaceutically acceptable inorganic or organic base,including, but not limited to organic bases such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like and inorganic bases such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. In addition, the salt forms of the disclosed compounds can beprepared using salts of the starting materials or intermediates.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein can be conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Polymorphs

In some embodiments, the compounds described herein exist as polymorphs.The invention provides for methods of treating diseases by administeringsuch polymorphs. The invention further provides for methods of treatingdiseases by administering such polymorphs as pharmaceuticalcompositions.

Thus, the compounds described herein include all their crystallineforms, known as polymorphs. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound. Incertain instances, polymorphs have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. In certaininstances, various factors such as the recrystallization solvent, rateof crystallization, and storage temperature cause a single crystal formto dominate.

Prodrugs

In some embodiments, the compounds described herein exist in prodrugform. The invention provides for methods of treating diseases byadministering such prodrugs. The invention further provides for methodsof treating diseases by administering such prodrugs as pharmaceuticalcompositions.

Prodrugs are generally drug precursors that, following administration toan individual and subsequent absorption, are converted to an active, ora more active species via some process, such as conversion by ametabolic pathway. Some prodrugs have a chemical group present on theprodrug that renders it less active and/or confers solubility or someother property to the drug. Once the chemical group has been cleavedand/or modified from the prodrug the active drug is generated. Prodrugsare often useful because, in some situations, they are easier toadminister than the parent drug. They are, for instance, bioavailable byoral administration whereas the parent is not. In certain instances, theprodrug also has improved solubility in pharmaceutical compositions overthe parent drug. An example, without limitation, of a prodrug would be acompound as described herein which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyamino acid) bonded to an acidgroup where the peptide is metabolized to reveal the active moiety. (Seefor example Bundgaard, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development, Krosgaard-Larsen and Bundgaard,Ed., 1991, Chapter 5, 113-191, which is incorporated herein byreference).

In some embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. The design of prodrugs to date has been toincrease the effective water solubility of the therapeutic compound fortargeting to regions where water is the principal solvent.

Additionally, prodrug derivatives of compounds described herein can beprepared by methods described herein are otherwise known in the art (forfurther details see Saulnier et al., Bioorganic and Medicinal ChemistryLetters, 1994, 4, 1985). By way of example only, appropriate prodrugscan be prepared by reacting a non-derivatized compound with a suitablecarbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds are prodrugs for another derivative or activecompound.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. The amino acid residues include but are notlimited to the 20 naturally occurring amino acids and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.In other embodiments, prodrugs include compounds wherein a nucleic acidresidue, or an oligonucleotide of two or more (e.g., two, three or four)nucleic acid residues is covalently joined to a compound of the presentinvention.

Pharmaceutically acceptable prodrugs of the compounds described hereinalso include, but are not limited to, esters, carbonates,thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,quaternary derivatives of tertiary amines, N-Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts andsulfonate esters. Compounds having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. In certaininstances, all of these prodrug moieties incorporate groups includingbut not limited to ether, amine and carboxylic acid functionalities.

Hydroxy prodrugs include esters, such as though not limited to,acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphateesters, sulfonate esters, sulfate esters and disulfide containingesters; ethers, amides, carbamates, hemisuccinates,dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews 1996, 19, 115.

Amine derived prodrugs include, but are not limited to the followinggroups and combinations of groups:

as well as sulfonamides and phosphonamides.

In certain instances, sites on any aromatic ring portions aresusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, can reduce,minimize or eliminate this metabolic pathway.

Pharmaceutical Compositions

Described herein are pharmaceutical compositions. In some embodiments,the pharmaceutical compositions comprise an effective amount of acompound of formula I, or a metabolite, pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. In someembodiments, the pharmaceutical compositions comprise an effectiveamount of a compound formula I, or a metabolite, pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereofand at least one pharmaceutically acceptable carrier. In someembodiments the pharmaceutical compositions are for the treatment ofdisorders. In some embodiments the pharmaceutical compositions are forthe treatment of disorders in a mammal. In some embodiments thepharmaceutical compositions are for the treatment of disorders in ahuman.

Modes of Administration

In some embodiments, the compounds and compositions described herein areadministered either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition. Administration of the compounds and compositions describedherein can be effected by any method that enables delivery of thecompounds to the site of action. These methods include, though are notlimited to delivery via enteral routes (including oral, gastric orduodenal feeding tube, rectal suppository and rectal enema), parenteralroutes (injection or infusion, including intraarterial, intracardiac,intradermal, intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant, said implant madefor example, out of a porous, non-porous, or gelatinous material,including membranes, such as silastic membranes, or fibers. Theadministration can also be by direct injection at the site of a diseasedtissue or organ.

In some embodiments, formulations suitable for oral administration arepresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. In some embodiments, the active ingredientis presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical preparations are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Pharmaceutical preparations may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical preparations may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical preparations may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical preparations suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation. It may however comprise as much as 10% w/wbut preferably will comprise less than 5% w/w, more preferably from 0.1%to 1% w/w of the formulation.

Pharmaceutical preparations for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Formulations

The compounds or compositions described herein can be delivered in avesicle, such as a liposome. The compounds and pharmaceuticalcompositions described herein can also be delivered in a controlledrelease system, or a controlled release system can be placed inproximity of the therapeutic target. In one embodiment, a pump may beused.

The pharmaceutical compositions described herein can also contain theactive ingredient in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use are optionally preparedaccording to known method, and such compositions may contain one or moreagents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,such as microcrystalline cellulose, sodium crosscarmellose, corn starch,or alginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be un-coatedor coated by known techniques to mask the taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, or cellulose acetate butyrate may be employed as appropriate.Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example olive oilor arachis oil, or a mineral oil, for example liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous solution. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. The sterile injectable preparation may also be a sterileinjectable oil-in-water microemulsion where the active ingredient isdissolved in the oily phase. For example, the active ingredient may befirst dissolved in a mixture of soybean oil and lecithin. The oilsolution then introduced into a water and glycerol mixture and processedto form a microemulsion. The injectable solutions or microemulsions maybe introduced into an individual's blood-stream by local bolusinjection. Alternatively, it may be advantageous to administer thesolution or microemulsion in such a way as to maintain a constantcirculating concentration of the instant compound. In order to maintainsuch a constant concentration, a continuous intravenous delivery devicemay be utilized. An example of such a device is the Deltec CADD-PLUS™model 5400 intravenous pump. The pharmaceutical compositions may be inthe form of a sterile injectable aqueous or oleagenous suspension forintramuscular and subcutaneous administration. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the active ingredient with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weights and fatty acid esters of polyethyleneglycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing a compound or composition of the invention can be used.As used herein, topical application can include mouth washes andgargles.

Pharmaceutical compositions may be administered in intranasal form viatopical use of suitable intranasal vehicles and delivery devices, or viatransdermal routes, using transdermal skin patches. To be administeredin the form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing into association a compound ofthe subject invention or a pharmaceutically acceptable salt, ester,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Dosage Forms

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionmay include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Doses

The amount of pharmaceutical composition administered will firstly bedependent on the mammal being treated. In the instances wherepharmaceutical compositions are administered to a human individual, thedaily dosage will normally be determined by the prescribing physicianwith the dosage generally varying according to the age, sex, diet,weight, general health and response of the individual, the severity ofthe individual's symptoms, the precise indication or condition beingtreated, the severity of the indication or condition being treated, timeof administration, route of administration, the disposition of thecomposition, rate of excretion, drug combination, and the discretion ofthe prescribing physician. Also, the route of administration may varydepending on the condition and its severity. Preferably, thepharmaceutical composition is in unit dosage form. In such form, thepreparation is subdivided into unit doses containing appropriatequantities of the active component, e.g., an effective amount to achievethe desired purpose. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with smaller dosages which are less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small amounts untilthe optimum effect under the circumstances is reached. For convenience,the total daily dosage may be divided and administered in portionsduring the day if desired. The amount and frequency of administration ofthe compounds described herein, and if applicable other therapeuticagents and/or therapies, will be regulated according to the judgment ofthe attending clinician (physician) considering such factors asdescribed above. Thus the amount of pharmaceutical composition to beadministered may vary widely. Administration may occur in an amount ofbetween about 0.001 mg/kg of body weight to about 100 mg/kg of bodyweight per day (administered in single or divided doses), morepreferably at least about 0.1 mg/kg of body weight per day. A particulartherapeutic dosage can include, e.g., from about 0.01 mg to about 7000mg of compound, and preferably includes, e.g., from about 0.05 mg toabout 2500 mg. The quantity of active compound in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg,preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg,according to the particular application. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, e.g. by dividing such largerdoses into several small doses for administration throughout the day.The amount administered will vary depending on the particular IC₅₀ valueof the compound used. In combinational applications in which thecompound is not the sole therapy, it may be possible to administerlesser amounts of compound and still have therapeutic or prophylacticeffect.

Combination Therapies

The compounds described herein or a pharmaceutically acceptable salt,solvate, polymorph, ester, tautomer or prodrug thereof may beadministered as a sole therapy. The compounds described herein or apharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof may also be administered in combination with anothertherapy or therapies.

For example, the therapeutic effectiveness of one of the compoundsdescribed herein may be enhanced by administration of an adjuvant (i.e.,by itself the adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the individual is enhanced). Or, by way of example only, thebenefit experienced by an individual may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for gout involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the individual withanother therapeutic agent for gout. Or, by way of example only, if oneof the side effects experienced by an individual upon receiving one ofthe compounds described herein is nausea, then it may be appropriate toadminister an anti-nausea agent in combination with the compound. Or,the additional therapy or therapies may include, but are not limited tophysiotherapy, psychotherapy, radiation therapy, application ofcompresses to a diseased area, rest, altered diet, and the like.Regardless of the disease, disorder or condition being treated, theoverall benefit experienced by the individual may be additive of the twotherapies or therapeutic agents or the individual may experience asynergistic benefit.

In the instances where the compounds described herein are administeredin combination with other therapeutic agents, the compounds describedherein need not be administered in the same pharmaceutical compositionas other therapeutic agents, and may, because of different physical andchemical characteristics, be administered by a different route. Forexample, the compounds/compositions may be administered orally togenerate and maintain good blood levels thereof, while the othertherapeutic agent may be administered intravenously. Thus the compoundsdescribed herein may be administered concurrently (e.g., simultaneously,essentially simultaneously or within the same treatment protocol),sequentially or dosed separately to other therapeutic agents. Theinitial administration can be made according to established protocolsknown in the art, and then, based upon the observed effects, the dosage,modes of administration and times of administration can be modified bythe skilled clinician.

The particular choice of compound and other therapeutic agent willdepend upon the diagnosis of the attending physicians and their judgmentof the condition of the individual and the appropriate treatmentprotocol. In some embodiments, the additional agent is a URAT 1inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, axanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase(PNP) inhibitor, a uric acid transporter inhibitor, a glucosetransporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrierfamily 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor,an organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, orcombinations thereof. In certain instances, URAT 1 is an ion exchangerthat mediates urate transportation. In certain instances, URAT Imediates urate transportation in the proximal tubule. In certaininstances, URAT I exchanges urate in a proximal tubule for lactate andnicotinate. In certain instances, xanthine oxidase oxidizes hypoxanthineto xanthine, and further to uric acid. In certain instances, xanthinedehydrogenase catalyzes the conversion of xanthine, NAD⁺, and H₂O intourate, NADH, and H⁺. In some embodiments, the additional agent isallopurinol, febuxostat(2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid),FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile),probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids,nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropichormone (ACTH), colchicine, a glucorticoid, an androgen, a cox-2inhibitor, a PPAR agonist, naproxen, sevelamer, sibutmaine,troglitazone, proglitazone, another uric acid lowering agent, losartan,fibric acid, benziodarone, salisylate, anlodipine, vitamin C, orcombinations thereof.

Diseases

Described herein are methods of treating a disease in an individualsuffering from said disease comprising administering to said individualan effective amount of a composition comprising a compound disclosedherein or a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Also described herein are methods of preventing or delaying onset of adisease in an individual at risk for developing said disease comprisingadministering to said individual an effective amount to prevent or delayonset of said disease, of a composition comprising a compound disclosedherein or a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Further described herein are methods for the prophylaxis or treatment ofany disease or disorder in which aberrant levels of uric acid plays arole including, without limitation: hyperuricemia, gout, goutyarthritis, inflammatory arthritis, kidney disease, nephrolithiasis(kidney stones), joint inflammation, deposition of urate crystals injoints, urolithiasis (formation of calculus in the urinary tract),deposition of urate crystals in renal parenchyma, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, gout flare, tophaceous gout, kidney failure,or combinations thereof in a human or other mammal. The methodsdisclosed herein extend to such a use and to the use of the compoundsfor the manufacture of a medicament for treating such diseases ordisorders. Further, the methods disclosed herein extend to theadministration to a human an effective amount of a compound disclosedherein for treating any such disease or disorder.

Individuals that can be treated with the compounds described herein, ora pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods of this inventioninclude, for example, individuals that have been diagnosed as havinggout, gouty arthritis, inflammatory arthritis, kidney disease,nephrolithiasis (kidney stones), joint inflammation, deposition of uratecrystals in joints, urolithiasis (formation of calculus in the urinarytract), deposition of urate crystals in renal parenchyma, Lesch-Nyhansyndrome, Kelley-Seegmiller syndrome, gout flare, tophaceous gout,kidney failure, or combinations thereof.

In some embodiments, an individual having an aberrant uric acid level isadministered an amount of at least one compound disclosed hereinsufficient to modulate the aberrant uric acid level (e.g., to amedically-acceptable level). In some embodiments, an individual treatedwith the compounds disclosed herein displays aberrant uric acid levelswherein the uric acid levels in blood exceed a medically-accepted range(i.e., hyperuricemia). In some embodiments, an individual treated withthe compounds disclosed herein displays aberrant uric acid levelswherein uric acid levels in the blood exceed 360 μmol/L (6 mg/dL) for afemale individual or 400 μmol/L (6.8 mg/dL) for a male individual.

In some embodiments, an individual treated with the compounds disclosedherein displays aberrant uric acid levels wherein uric acid levels inurine exceed a medically-accepted range (i.e., hyperuricosuria). In someembodiments, an individual treated with the compounds disclosed hereindisplays aberrant uric acid levels wherein uric acid levels in urineexceed 800 mg/day (in a male individual) and greater than 750 mg/day (ina female individual).

In some embodiments, an individual treated with the compounds disclosedherein (1) displays aberrant uric acid levels, and (2) suffers from acardiovascular disorder. In some embodiments, an individual treated withthe compounds disclosed herein (1) displays aberrant uric acid levels,and (2) suffers from an aneurysm; angina; atherosclerosis; a stroke;cerebrovascular disease; congestive heart failure; coronary arterydisease; and/or a myocardial infarction. In some embodiments, anindividual treated with the compounds disclosed herein (1) displaysaberrant uric acid levels, and (2) displays (a) c-reactive protein (CRP)levels above about 3.0 mg/L; (b) homocysteine levels above about 15.9mmol/L; (c) LDL levels above about 160 mg/dL; (d) HDL levels below about40 mg/dL; and/or (e) serum creatinine levels above about 1.5 mg/dL.

In some embodiments, an individual treated with the compounds disclosedherein (1) displays aberrant uric acid levels, and (2) suffers fromdiabetes. In some embodiments, an individual treated with the compoundsdisclosed herein (1) displays aberrant uric acid levels, and (2) suffersfrom Type I diabetes. In some embodiments, an individual treated withthe compounds disclosed herein (1) displays aberrant uric acid levels,and (2) suffers from Type II diabetes. In some embodiments, anindividual treated with the compounds disclosed herein (1) displaysaberrant uric acid levels, and (2) suffers from a loss of beta cells ofthe islets of Langerhans in the pancreas. In some embodiments, anindividual treated with the compounds disclosed herein (1) displaysaberrant uric acid levels, and (2) suffers from insulin resistanceand/or reduced insulin sensitivity. In some embodiments, an individualtreated with the compounds disclosed herein (1) displays aberrant uricacid levels, and (2) displays (a) a fasting plasma glucose level ≧126mg/dL; (b) a plasma glucose level ≧200 mg/dL two hours after a glucosetolerance test; and/or (c) symptoms of hyperglycemia and casual plasmaglucose levels ≧200 mg/dL (11.1 mmol/l).

In some embodiments, an individual treated with the compounds disclosedherein (1) displays aberrant uric acid levels, and (2) suffers frommetabolic syndrome. In some embodiments, an individual treated with thecompounds disclosed herein (1) displays aberrant uric acid levels, and(2) suffers from (a) diabetes mellitus, impaired glucose tolerance,impaired fasting glucose and/or insulin resistance, (b) at least two of(i) blood pressure: ≧140/90 mmHg; (ii) dyslipidaemia: triglycerides(TG): ≧1.695 mmol/L and high-density lipoprotein cholesterol (HDL-C)≦0.9 mmol/L (male), ≦1.0 mmol/L (female); (iii) central obesity:waist:hip ratio>0.90 (male); >0.85 (female), and/or body mass index >30kg/m2; and (iv) microalbuminuria: urinary albumin excretion ratio >20mg/min or albumin:creatinine ratio ≧30 mg/g. In some embodiments, anindividual treated with the compounds disclosed herein (1) displaysaberrant uric acid levels, and (2) suffers from insulin resistance(i.e., the top 25% of the fasting insulin values among non-diabeticindividuals) and (b) at least two of (i) central obesity: waistcircumference ≧94 cm (male), ≧80 cm (female); (ii) dyslipidaemia: TG≧2.0mmol/L and/or HDL-C<1.0 mmol/L or treated for dyslipidaemia; (iii)hypertension: blood pressure ≧140/90 mmHg or antihypertensivemedication; and (iv) fasting plasma glucose ≧6.1 mmol/L. In someembodiments, an individual treated with the compounds disclosed herein(1) displays aberrant uric acid levels, and (2) displays at least threeof (a) elevated waist circumference: Men ≧40 inches (men) and ≧35 inches(women); (b) elevated triglycerides: ≧150 mg/dL; (c) reduced HDL: <40mg/dL (men) and <50 mg/dL (women); (d) elevated blood pressure: ≧130/85mm Hg or use of medication for hypertension; and (e) elevated fastingglucose: ≧100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia.

In some embodiments, an individual treated with the compounds disclosedherein (1) displays aberrant uric acid levels, and (2) suffers fromkidney disease or kidney failure. In some embodiments, an individualtreated with the compounds disclosed herein (1) displays aberrant uricacid levels, and (2) displays oliguria (decreased urine production. Insome embodiments, an individual treated with the compounds disclosedherein (1) displays aberrant uric acid levels, and (2) produces lessthan 400 mL per day of urine (adults), produces less than 0.5 mL/kg/h ofurine (children), or produces less than 1 mL/kg/h of urine (infants).

Uric Acid

In certain instances, purines (adenine, guanine), derived from food ortissue turnover (cellular nucleotides undergo continuous turnover), arecatabolized in humans to their final oxidation product, uric acid. Incertain instances, guanine is oxidized to xanthine, which is turn isfurther oxidized to uric acid by the action of xanthine oxidase;adenosine is converted to inosine which is further oxidized tohypoxanthine. In certain instances, xanthine oxidase oxidizeshypoxanthine to xanthine, and further to uric acid. In certaininstances, as part of the reverse process, the enzymehypoxanthine-guanine phosphoribosyltransferase (HGPRT) salvages guanineand hypoxanthine.

In certain instances, the keto form of uric acid is in equilibrium withthe enol form which loses a proton at physiological pH to form urate. Incertain instances, (e.g., under serum conditions (pH 7.40, 37° C.)),about 98% of uric acid is ionized as the monosodium urate salt. Incertain instances, urate is a strong reducing agent and potentantioxidant. In humans, about half the antioxidant capacity of plasmacomes from uric acid.

In certain instances, most uric acid dissolves in blood and passes tothe kidneys, where it is excreted by glomerular filtration and tubularsecretion. In certain instances, a substantial fraction of uric acid isreabsorbed by the renal tubules. One of the peculiar characteristics ofthe uric acid transport system is that, although the net activity oftubular function is reabsorption of uric acid, the molecule is bothsecreted and reabsorbed during its passage through the nephron. Incertain instances, reabsorption dominates in the S1 and S3 segments ofthe proximal tubule and secretion dominates in the S2 segment. Incertain instances, the bidirectional transport results in drugs thatinhibit uric acid transport decreasing, rather than increasing, theexcretion of uric acid, compromising their therapeutic usefulness. Incertain instances, normal uric acid levels in human adults (5.1+/−0.93mg/dL) are close to the limits of urate solubility (˜7 mg/dL at 37° C.),which creates a delicate physiologic urate balance. In certaininstances, the normal uric acid range for females is approximately 1mg/dL below the male range.

Hyperuricemia

In certain instances, hyperuricemia is characterized by higher thannormal blood levels of uric acid, sustained over long periods of time.In certain instances, increased blood urate levels may be due toenhanced uric acid production (10-20%) and/or reduced renal excretion(˜80-90%) of uric acid.

In certain instances, causes of hyperuricemia may include:

Obesity/weight gain

Excessive alcohol use

Excessive dietary purine intake (foods such as shellfish, fish roe,scallops, peas lentils, beans and red meat, particularly offal—brains,kidneys, tripe, liver)

Certain medications, including low-dose aspirin, diuretics, niacin,cyclosporine, pyrazinamide, ethambutol, some high blood pressure drugsand some cancer chemotherapeutics, immunosuppressive and cytotoxicagents

Specific disease states, particularly those associated with a high cellturnover rate (such as malignancy, leukemia, lymphoma or psoriasis), andalso including high blood pressure, hemoglobin disorders, hemolyticanemia, sickle cell anemia, various nephropathies, myeloproliferativeand lymphoproliferative disorders, hyperparathyroidism, renal disease,conditions associated with insulin resistance and diabetes mellitus, andin transplant recipients, and possibly heart disease

Inherited enzyme defects

Abnormal kidney function (e.g. increased ATP turn over, reducedglomerular urate filtration)

Exposure to lead (plumbism or “saturnine gout”)

In certain instances, hyperuricemia may be asymptomatic, though isassociated with the following conditions:

Gout

Gouty arthritis

Uric acid stones in the urinary tract (urolithiasis)

Deposits of uric acid in the soft tissue (tophi)

Deposits of uric acid in the kidneys (uric acid nephropathy)

Impaired kidney function, possibly leading to chronic and acute renalfailure

Gout

Prevalence

The incidence of gout has increased over the past two decades and, inthe United States, affects as much as 2.7% of the population aged 20years and older, totaling over 5.1 million American adults. Gout is morecommon in men than women, (3.8% or 3.4 million men vs. 1.6% or 1.7million women), typically affecting men in their 40's and 50's (althoughgout attacks can occur after puberty which sees an increase in uric acidlevels). An increase in prevalence of gout from 2.9 to 5.2 per 1000 inthe time period 1990 to 1999 was observed, with most of the increaseoccurring in those over the age of 65. Gout attacks are more common inwomen after menopause. In certain instances, gout is one of the mostcommon forms of arthritis, accounting for approximately 5% of allarthritis cases. In certain instances, kidney failure and urolithiasisoccur in 10-18% of individuals with gout and are common sources ofmorbidity and mortality from the disease.

Leading Causes

In most cases, gout is associated with hyperuricemia. In certaininstances, individuals suffering from gout excrete approximately 40%less uric acid than nongouty individuals for any given plasma urateconcentrations. In certain instances, urate levels increase until thesaturation point is reached. In certain instances, precipitation ofurate crystals occurs when the saturation point is reached. In certaininstances, these hardened, crystallized deposits (tophi) form in thejoints and skin, causing joint inflammation (arthritis). In certaininstances, deposits are be made in the joint fluid (synovial fluid)and/or joint lining (synovial lining). Common areas for these depositsare the large toe, feet, ankles and hands (less common areas include theears and eyes). In certain instances, the skin around an affected jointbecomes red and shiny with the affected area being tender and painful totouch. In certain instances, gout attacks increase in frequency. Incertain instances, untreated acute gout attacks lead to permanent jointdamage and disability. In certain instances, tissue deposition of urateleads to: acute inflammatory arthritis, chronic arthritis, deposition ofurate crystals in renal parenchyma and urolithiasis. In certaininstances, the incidence of gouty arthritis increases 5 fold inindividuals with serum urate levels of 7 to 8.9 mg/dL and up to 50 foldin individuals with levels >9 mg/dL (530 μmol/L). In certain instances,individuals with gout develop renal insufficiency and end stage renaldisease (i.e., “gouty nephropathy”). In certain instances, goutynephropathy is characterized by a chronic interstitial nephropathy,which is promoted by medullary deposition of monosodium urate.

In certain instances, gout includes painful attacks of acute,monarticular, inflammatory arthritis, deposition of urate crystals injoints, deposition of urate crystals in renal parenchyma, urolithiasis(formation of calculus in the urinary tract), and nephrolithiasis(formation of kidney stones). In certain instances, secondary goutoccurs in individuals with cancer, particularly leukemia, and those withother blood disorders (e.g. polycythemia, myeloid metaplasia, etc).

Symptoms

In certain instances, attacks of gout develop very quickly, frequentlythe first attack occurring at night. In certain instances, symptomsinclude sudden, severe joint pain and extreme tenderness in the jointarea, joint swelling and shiny red or purple skin around the joint. Incertain instances, the attacks are infrequent lasting 5-10 days, with nosymptoms between episodes. In certain instances, attacks become morefrequent and may last longer, especially if the disorder is notcontrolled. In certain instances, episodes damage the affected joint(s)resulting in stiffness, swelling, limited motion and/or persistent mildto moderate pain.

Treatment

In certain instances, gout is treated by lowering the production of uricacid. In certain instances, gout is treated by increasing the excretionof uric acid. In certain instances, gout is treated by URAT 1, xanthineoxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purinenucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT)inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, asolute carrier family 2 (facilitated glucose transporter), member 9(SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, anOAT-4 inhibitor, or combinations thereof. In general, the goals of gouttreatment are to i) reduce the pain, swelling and duration of an acuteattack, and ii) prevent future attacks and joint damage. In certaininstances, gout attacks are treated successfully using a combination oftreatments. In certain instances, gout is one of the most treatableforms of arthritis.

i) Treating the gout attack. In certain instances, the pain and swellingassociated with an acute attack of gout can be addressed withmedications such as acetaminophen, steroids, nonsteroidalanti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH) orcolchicine. In certain instances, proper medication controls gout within12 to 24 hours and treatment is stopped after a few days. In certaininstances, medication is used in conjunction with rest, increased fluidintake, ice-packs, elevation and/or protection of the affected area/s.In certain instances, the aforementioned treatments do not preventrecurrent attacks and they do not affect the underlying disorders ofabnormal uric acid metabolism.

ii) Preventing future attacks. In certain instances, reducing serum uricacid levels below the saturation level is the goal for preventingfurther gout attacks. In some cases, this is achieved by decreasing uricacid production (e.g. allopurinol), or increasing uric acid excretionwith uricosuric agents (e.g. probenecid, sulfinpyrazone, benzbromarone).

In certain instances, allopurinol inhibits uric acid formation,resulting in a reduction in both the serum and urinary uric acid levelsand becomes fully effective after 2 to 3 months.

In certain instances, allopurinol is a structural analogue ofhypoxanthine, (differing only in the transposition of the carbon andnitrogen atoms at positions 7 and 8), which inhibits the action ofxanthine oxidase, the enzyme responsible for the conversion ofhypoxanthine to xanthine, and xanthine to uric acid. In certaininstances, it is metabolized to the corresponding xanthine analogue,alloxanthine (oxypurinol), which is also an inhibitor of xanthineoxidase. In certain instances, alloxanthine, though more potent ininhibiting xanthine oxidase, is less pharmaceutically acceptable due tolow oral bioavailability. In certain instances, fatal reactions due tohypersensitivity, bone marrow suppression, hepatitis, and vasculitishave been reported with Allopurinol. In certain instances, the incidenceof side effects may total 20% of all individuals treated with the drug.Treatment for disorders of uric acid metabolism has not evolvedsignificantly in the following two decades since the introduction ofallopurinol.

In certain instances, Uricosuric agents (e.g., probenecid,sulfinpyrazone, and benzbromarone) increase uric acid excretion. Incertain instances, probenecid causes an increase in uric acid secretionby the renal tubules and, when used chronically, mobilizes body storesof urate. In certain instances, 25-50% of individuals treated withprobenecid fail to achieve reduction of serum uric acid levels <6 mg/dL.In certain instances, insensitivity to probenecid results from drugintolerance, concomitant salicylate ingestion, and renal impairment. Incertain instances, one-third of the individuals develop intolerance toprobenecid. In certain instances, administration of uricosuric agentsalso results in urinary calculus, gastrointestinal obstruction, jaundiceand anemia.

Plumbism or “Saturnine Gout”

In certain instances, excessive exposure to lead (lead poisoning orplumbism) results in “saturnine gout,” a lead-induced hyperuricemia dueto lead inhibition of tubular urate transport causing decreased renalexcretion of uric acid. In certain instances, more than 50% ofindividuals suffering from lead nephropathy suffer from gout. In certaininstances, acute attacks of saturnine gout occur in the knee morefrequently than the big toe. In certain instances, renal disease is morefrequent and more severe in saturnine gout than in primary gout. Incertain instances, treatment consists of excluding the individual fromfurther exposure to lead, the use of chelating agents to remove lead,and control of acute gouty arthritis and hyperuricemia. In certaininstances, saturnine gout is characterized by less frequent attacks thanprimary gout. In certain instances, lead-associated gout occurs inpre-menopausal women, an uncommon occurrence in non lead-associatedgout.

Lesch-Nyhan Syndrome

In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's syndrome)affects about one in 100,000 live births. In certain instances, LNS iscaused by a genetic deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HGPRT). In certain instances, LNS is anX-linked recessive disease. In certain instances, LNS is present atbirth in baby boys. In certain instances, the disorder leads to severegout, poor muscle control, and moderate mental retardation, which appearin the first year of life. In certain instances, the disorder alsoresults in self-mutilating behaviors (e.g., lip and finger biting, headbanging) beginning in the second year of life. In certain instances, thedisorder also results in gout-like swelling in the joints and severekidney problems. In certain instances, the disorder leads neurologicalsymptoms include facial grimacing, involuntary writhing, and repetitivemovements of the arms and legs similar to those seen in Huntington'sdisease. The prognosis for individuals with LNS is poor. In certaininstances, the life expectancy of an untreated individual with LNS isless than about 5 years. In certain instances, the life expectancy of atreated individual with LNS is greater than about 40 years of age.

Hyperuricemia and Other Diseases

In certain instances, hyperuricemia is found in individuals withcardiovascular disease (CVD) and/or renal disease. In certain instances,hyperuricemia is found in individuals with prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congenative heart failure, stroke, tumor lysis syndromeendothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.In certain instances, hyperuricemia is found in individuals with obesity(e.g., central obesity), high blood pressure, hyperlipidemia, and/orimpaired fasting glucose. In certain instances, hyperuricemia is foundin individuals with metabolic syndrome. In certain instances, goutyarthritis is indicative of an increased risk of acute myocardialinfarction. In some embodiments, administration of the compoundsdescribed herein to an individual are useful for decreasing thelikelihood of a clinical event associated with a disease or conditionlinked to hyperuricemia, including, but not limited to, prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congenative heart failure, stroke, tumor lysissyndrome, endothelial dysfunction, oxidative stress, elevated reninlevels, elevated endothelin levels, and/or elevated C-reactive proteinlevels.

In some embodiments, the compounds described herein are administered toan individual suffering from a disease or condition requiring treatmentwith a compound that is a diuretic. In some embodiments, the compoundsdescribed herein are administered to an individual suffering from adisease or condition requiring treatment with a compound that is adiuretic, wherein the diuretic causes renal retention of urate. In someembodiments, the disease or condition is congestive heart failure oressential hypertension.

In some embodiments, administration of the compounds described herein toan individual are useful for improving motility or improving quality oflife.

In some embodiments, administration of the compounds described herein toan individual is useful for treating or decreasing the side effects ofcancer treatment.

In some embodiments, administration of the compounds described herein toan individual is useful for decreasing kidney toxicity of cis-platin.

Kits

The compounds, compositions and methods described herein provide kitsfor the treatment of disorders, such as the ones described herein. Thesekits comprise a compound, compounds or compositions described herein ina container and, optionally, instructions teaching the use of the kitaccording to the various methods and approaches described herein. Suchkits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in some embodiments,be marketed directly to the consumer.

The compounds described herein can be utilized for diagnostics and asresearch reagents. For example, the compounds described herein, eitheralone or in combination with other compounds, can be used as tools indifferential and/or combinatorial analyses to elucidate expressionpatterns of genes expressed within cells and tissues. As onenon-limiting example, expression patterns within cells or tissuestreated with one or more compounds are compared to control cells ortissues not treated with compounds and the patterns produced areanalyzed for differential levels of gene expression as they pertain, forexample, to disease association, signaling pathway, cellularlocalization, expression level, size, structure or function of the genesexamined. These analyses can be performed on stimulated or unstimulatedcells and in the presence or absence of other compounds which affectexpression patterns.

Besides being useful for human treatment, the compounds and formulationsof the present invention are also useful for veterinary treatment ofcompanion animals, exotic animals and farm animals, including mammals,rodents, and the like. More preferred animals include horses, dogs, andcats.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

EXAMPLES I Chemical Syntheses Example 12-(4-(2,4-Dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)aceticAcid

Step A: Ethyl 2-bromoacetate (68 μL, 0.611 mmol) and potassium carbonate(0.17 g, 1.22 mmol) were added to a solution of4-(2,4-Dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol(0.2 g, 0.611 mmol) in THF (2.44 mL). The resulting mixture was heatedat 60° C. for 18 hours. The mixture was concentrated, ethyl2-bromoacetate (68 μL, 0.611 mmol) and DMF (1.2 mL) added, and themixture heated at 60° C. for 24 hours. Water (40 mL) was added and themixture extracted with ethyl acetate (2×40 mL). The combined organicextracts were washed with brine, dried over sodium sulfate, filtered,concentrated and purified by SGC (0-50% ethyl acetate/Hexanes) to affordethyl2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetateas a clear oil (0.137 g, 54%).

Step B: Lithium hydroxide solution (1M aqueous, 0.436 mL, 0.436 mmol)was added to a solution of ethyl2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetate(0.09 g, 0.218 mmol) in THF/methanol/water (3/3/1, 1.5 mL) and stirredfor 18 h at room temperature. The crude reaction mixture wasconcentrated, acidified with HCl (1M aqueous, 4 mL), and extracted withethyl acetate (2×3 mL). The combined organics extracts were concentratedto afford2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)aceticacid as an off-white foam (0.082 g, 98%).

Example 22-(4-(4,7-Dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic Acid

Step A: Ethyl 2-bromoacetate (87 μL, 0.783 mmol) and Potassium carbonate(0.216 g, 1.57 mmol) were added to a solution of4-(4,7-Dimethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.783mmol) in THF (3.1 mL). The resulting mixture was then heated to 60° C.for 1 hour. Additional DMF (1 mL) was added and the mixture heated at60° C. for 18 hours. Water (3 mL) was added and the mixture extractedwith ethyl acetate (3×3 mL). The combined organic extracts were driedover sodium sulfate, filtered, concentrated and Purified by SGC (0-100%EtOAc/Hexanes) to afford ethyl2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate asa clear oil (0.231 g, 86%).

Step B: Lithium hydroxide solution (1M aqueous, 0.88 mL, 0.488 mmol) wasadded to a solution of 4 ethyl2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(0.15 g, 0.44 mmol) in THF/ethanol/water (1:1:1, 7 mL) and the mixturestirred for 2 h at room temperature. The crude reaction mixture was thenconcentrated, acidified with HCl (1M, 3 mL) and extracted with ethylacetate (3×5 mL). The combined organics extracts were concentrated toafford2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acidas an off-white solid (0.129 g, 94%).

Example 32-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicAcid

Step A: 3-Bromo-propionic acid ethyl ester (158 μL, 224 mg; 1.239 mmol)was added to a solution of5-Amino-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol(0.35 g, 1.239 mmol) in DMF (2.5 mL). The resulting mixture was heatedto 60° C. for 20 hours. The reaction mixture was concentrated andsonicated with ethyl ether several times, decanting the ethyl etherlayer. The resulting light yellow oil was placed on high vacuum toafford crude ethyl3-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoateas a light brown oily foam which was used directly in the next step(0.409 g, 87%).

Step B:3-(5-Amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate,(200 mg 0.523 mmol), sodium nitrite (361 mg, 5.233 mmol, 10 eq.) andbenzyltriethylammonium bromide (427 mg, 1.570 mmol, 3 eq.) weresuspended in bromoform (3 mL) and stirred at room temperature for 30min. Dichloroacetic acid was then added (86 μL, 135 mg; 1.047 mmol, 2eq.), and the mixture stirred at room temperature overnight, coveringthe flask with foil to keep light out. Water was added (5 mL) andstirring continued for a further 30 min. The reaction mixture was thentransferred to a sep. funnel and additional water and dichloromethanewere added. The organic layer was collected and the aqueous layer washedwith dichloromethane (2×). The combined organic extracts were dried oversodium sulfate, filtered, concentrated and purified by flash columnchromatography (6:4 Hexanes/Ethyl acetate) to give ethyl3-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoateas a light brown oil (111 mg, 47.6%).

Step C: Aqueous lithium hydroxide solution (1M, 437 μL, 0.437 mmol, 3eq.) was added to a solution of ethyl3-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate(65 mg, 0.146 mmol) in THF (1.5 mL) and methanol (1 mL). The mixture wasstirred at room temperature for 2 hours, and HCl (1N, 584 μL, 0.584mmol, 4 eq.) added. The mixture was concentrated, a little water added,sonicated and the off-white solids isolated by filtration. The isolatedmaterial was placed into small amount of methanol, sonicated again, andthen filtered to give5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol as anoff-white solid (39 mg, 78%).

Step D: A solution of5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (50mg, 0.144 mmol), ethyl 2-bromo-2-methylpropanoate (22 μL, 0.144 mmol)and diisopropylethylamine (76 μL, 0.433 mmol) in DMF (1 mL) was heatedto 60° C. for 20 hours. The mixture was then concentrated, sonicated inethyl ether until fully dissolved, and washed with 1N HCl. The mixturewas extracted with diethyl ether (2×5 mL), and the combined organicextracts dried over sodium sulfate, filtered, and concentrated toprovide ethyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoateas a brown oil (60 mg, 91%).

Step E: Lithium hydroxide solution (1M aqueous, 358 μL, 0.358 mmol, 3eq) was added to a solution of ethyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate(55 mg, 0.119 mmol) in THF (1 mL) and methanol (0.5 mL), and the mixturestirred for 2 hours at room temperature. The crude reaction mixture wasthen concentrated, acidified with HCl (1N) and sonicated to break upsolids. Filtration gave2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicacid as an off-white solid (39 mg, 76%).

Example 42-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticAcid

Step A: Triethylamine (0.11 mL, 0.786 mmol) and ethyl 2-bromoacetate (80μL, 0.72 mmol) were added to a stirred solution of5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol(0.2 g, 0.655 mmol) in dichloromethane (2.6 mL). The resulting mixturewas stirred for 2 h. The crude reaction mixture was purified by SGC(0-50% EtOAc/Hexanes) to afford ethyl2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateas an off-white solid (0.246 g, 96%).

Step B: Lithium hydroxide solution (1M aqueous, 0.77 mL, 0.77 mmol) wasadded to a solution of ethyl2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(0.15 g, 0.38 mmol) in THF/water (3:1, 1.5 mL) and the mixture stirredfor 8 h at room temperature. The crude reaction mixture was thenconcentrated and acidified with HCl (1N, 3 mL) and extracted with ethylacetate (3×2 mL). The combined organic extracts were concentrated toafford2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid as an off-white foam (0.136 g, 99%).

Example 52-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicAcid

Step A: Ethyl 2-bromo-2-methylpropanoate (184 μL, 1.239 mmol) was addedto a solution of5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.35g, 1.239 mmol) in DMF (2.5 mL) and heated at 60° C. for 20 hours afterwhich time a few crystals of potassium iodide were added and the mixtureheated at 70° C. for a further 24 h. The temperature was then increasedto 90° C. and the mixture heated for an additional 6 days. The mixturewas allowed to cool to room temperature, concentrated and dissolved indichloromethane. Triethylamine and water were added and the layersseparated. The aqueous layer was extracted with dichloromethane (2×) andthe combined organic extracts dried over NaSO₄, filtered, concentratedand purified by column chromatography (ethyl acetate) to afford ethyl2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoateas a tan solid (0.134 g, 27%).

Step B: Lithium hydroxide solution (1M aqueous, 0.757 mL, 0.757 mmol)was added to a solution of ethyl2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate(100 mg, 0.252 mmol) in THF (2 mL) and methanol (1 mL) and the mixturestirred at room temperature for 20 h. The crude reaction mixture wasacidified with HCl (1N, 1 mL) and sonicated to break up the solids,which were then isolated by filtration to give2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicacid as a white solid (69 mg, 74%).

Example 62-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4triazol-3-ylthio)acetic Acid

Step A: Triethylamine (0.087 mL, 0.623 mmol) and ethyl 2-bromoacetate(63 μL, 0.571 mmol) were added to a solution of5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol(0.144 g, 0.519 mmol) in dichloromethane (2.1 mL) and stirred at roomtemperature for 2 hours. The crude reaction mixture was purified by SGC(0-100% EtOAc/Hexanes) to afford ethyl2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateas an off-white solid (0.168 g, 89%).

Step B: Lithium hydroxide solution (1M aqueous, 0.59 mL, 0.59 mmol) isadded to a solution of ethyl2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate(107 mg, 0.294 mmol) in THF/water (3/1, 1.2 mL) and the mixture stirredat room temperature for 18 h. The crude reaction mixture isconcentrated, acidified with HCl (1N, 3 mL) and extracted with ethylacetate (3×3 mL). The combined organic extracts are dried over sodiumsulfate, filtered and concentrated to afford2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid.

Example 7 tert-Butyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate

A solution of5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol(prepared as described above; 500 mg, 1.444 mmol) and tert-butyl2-bromo-2-methylpropanoate (270 μL, 1.444 mmol) anddiisopropylethylamine (755 μL, 4.332 mmol) in DMF (3 mL) was heated at60° C. for 20 hours. The mixture was then concentrated, diethyl ether(15 mL) was added and the mixture was sonicated until all solidsdissolved. The solution was then washed with HCl with (1N, 10 mL) andextracted with diethyl ether (2×15 mL). The combined organic extractswere dried over sodium sulfate, filtered, and concentrated to affordtert-butyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoateas a light brown foam (532 mg, 75% yield).

Example 82-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticAcid

Sodium hydroxide solution (2M aqueous, 33.7 mL, 67 mmol, 2 eq) was addedto a suspension of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-(2-chloro-4-sulfamoylphenyl)acetamide(prepared by previously published procedures; 20 g, 34 mmol) in ethanol(200 mL) and the mixture heated at reflux for 4 hours. Charcoal (10 g)was added, the mixture stirred at room temperature for 12 hours and thecharcoal removed by filtration. The charcoal was washed several timeswith ethanol and the filtrate then concentrated. Water (200 mL) wasadded and then concentrated to approx. one third volume, to remove allethanol. Water (200 mL) and ethyl acetate (250 mL) were added, themixture stirred vigorously for 15 mins and the organic layer removed.The aqueous layer was cooled to 0° C. and acidified by treatment withHCl (IN) resulting in the formation of a cloudy oily precipitate. Themixture was extracted with ethyl acetate (3×) and the combined organicextracts dried over sodium sulfate and concentrated to give2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid as an off white solid (11.2 g, 82%).

Example 92-(4-(4-Cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicAcid

Step A: Ethyl 2-bromo-2-methylpropanoate (89 μL, 0.596 mmol) anddiisopropylethylamine (0.31 mL, 1.789 mmol) were added to a solution of4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol(0.2 g, 0.596 mmol) in DMF (1.2 mL) and the mixture heated at 60° C. for20 hours. The mixture was concentrated, acidified with HCl (1M aqueous,2 mL) and extracted with ethyl acetate (3×3 mL). The combined organicextracts were dried over sodium sulfate, concentrated and purified bycolumn chromatography (0-25% EtOAc/hexanes) to provide ethyl2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoateas a clear oil (0.1 g, 37%).

Step B: Lithium hydroxide solution (1M aqueous, 0.67 mL, 0.67 mmol) wasadded to a solution of ethyl2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate(0.1 g, 0.22 mmol) in THF (0.88 mL) and the mixture stirred at roomtemperature for 18 h. The crude reaction mixture was concentrated; water(100 mL) added and then washed with ethyl acetate (2×40 mL). The aqueouslayer was acidified with HCl (1N aqueous, 10 mL) and extracted withethyl acetate (30 mL). The combined organic extracts were dried oversodium sulfate and concentrated to afford2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicacid as an off-white solid (49 mg, 53%).

Example 101-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylicAcid

Step A: A solution of5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (100mg, 0.289 mmol), ethyl 1-bromocyclobutanecarboxylate (47 μL, 0.289 mmol)and diisopropylethylamine (151 μL, 0.866 mmol) in DMF (1 mL) was heatedat 60° C. for 4 days. After cooling to room temperature, the mixture wasconcentrated and partitioned between dichloromethane (15 mL) and HCl (1Naqueous, 15 mL). The aqueous layer was extracted with dichloromethane(2×15 mL) and the combined organic extracts dried over sodium sulfate,concentrated and purified by column chromatography (40% EtOAc/hexanes)to provide ethyl1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylateas a light yellow sticky foam (75 mg, 55% yield).

Step B: Lithium hydroxide solution (1M aqueous, 0.387 mL, 0.387 mmol, 3eq) was added to a solution of ethyl1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylate(61 mg, 0.129 mmol) in THF/methanol (2/1, 3 mL) and the mixture stirredat room temperature for 18 h. The mixture was acidified with HCL (1Naqueous, 0.645 mL, 0.645 mmol, 5 eq), concentrated, water (110 mL) addedand extracted with diethyl ether (2×15 mL). The combined organicextracts were dried over calcium chloride and concentrated to give1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylicacid as an off-white solid (43 mg, 75%).

Example 11

Several compounds of formula (I) were prepared according to theprotocols described in the previous examples. The analytical data forthese compounds are given in the table below.

II Biological Evaluation Example 12 Uric Acid Uptake Assay

Creation of Stable Cell Lines Expressing hURAT1 Transporter: Full-lengthhuman URAT1 gene (SLC22A12) was subcloned from plasmid pCMV6-XL5(Origene) into eukaryotic expression plasmid pCMV6/Neo (Origene) usingNot I restriction sites. Gene sequencing confirmed the sequence ofhURAT1 as outlined in Genbank (Accession #NM_(—)144585.2). HEK293 humanembryonic kidney cells (ATCC# CRL-1573) were propagated in EMEM tissueculture medium as described by ATCC in an atmosphere of 5% CO₂ and 95%air. Transfections of HEK293 cells with the pCMV6/Neo/URAT1 constructwere performed using L2000 transfection reagent (Invitrogen) asdescribed by the manufacturer. After 24 h the transfected cells weresplit into 10 cm tissue culture plates and grown for 1 day after whichthe medium was replaced with fresh growth medium containing G418 (Gibco)at 0.5 mg/ml final concentration. Drug-resistant colonies were selectedafter approximately 8 days and then tested for ¹⁴C-uric acid transportactivity. The HEK293/urat1 cells are plated on Poly-D-Lysine Coated96-well Plates at a density of 75,000 cells per well.

Cells were grown overnight (20-26 hours) at 37° C. in an incubator.Plates were allowed to come to room temperature and media was washed outwith one wash of 250 μl of Wash Buffer (125 mM Na Gluconate, 10 mM Hepesph 7.3). Compound or vehicle was added in assay buffer with C14 UricAcid for a final concentration of 40 μM Uric Acid with a specificactivity of 54 mCi/mmol. Assay Buffer was 125 mM Sodium Gluconate, 4.8mM Potassium Gluconate, 1.2 mM Potassium phosphate, monobasic, 1.2 mMmagnesium sulfate, 1.3 mM Ca Gluconate, 5.6 mM Glucose, 25 mM HEPES, pH7.3. Plates were incubated at room temperature for 10 minutes thenwashed 3 times with 50 μl Wash Buffer and 3 times with 250 μl WashBuffer. Microscint 20 Scintillation Fluid was added and plates wereincubated overnight at 45° C. to equilibrate. Plates were then read onthe TopCount Plate Reader and an EC50 value generated. (See Enomoto etal, Nature, 2002, 417, 447-451 and Anzai et al, J. Biol. Chem., 2004,279, 45942-45950.)

Compounds of formula (I), prepared as described above in examples 1-11,were examined according to the procedure described above and EC₅₀ valuesgenerated. The table below summarizes the activity of the compounds inthe Uric Acid Uptake Assay, wherein A represents an EC₅₀ from 1 nM to 1μM; B represents an EC₅₀ from 1 μM to 30 μM; and C represents an EC₅₀greater than 30 μM. (N/A means data not available).

Activity Eg Structure NMR Chemical Shifts MS (EC₅₀)  1A

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J = 7.15 Hz, 3 H)1.64-1.93 (m, 4 H) 2.25 (s, 3 H) 2.31 (s, 3 H) 2.52-2.68 (m, 3 H)2.76-2.87 (m, 1 H) 4.29 (q, J = 7.26 Hz, 2 H) 4.35-4.59 (m, 2 H) 7.30(s, 1 H) Mass found: 414.05 (M + 1) C  1B

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.65 (m, 1 H) 1.65-1.83 (m, 3 H)2.21 (s, 3 H) 2.24 (s, 3 H) 2.34-2.47 (m, 1 H) 2.60 (t, J = 5.91 Hz, 2H) 2.80- 2.93 (m, 1 H) 4.38-4.56 (m, 2 H) 7.07 (s, 1 H) 12.97 (br. s., 1H) Mass found: 386.04 (M + 1) B  2A

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (t, 3 H) 2.45 (s, 3 H) 2.75 (s, 3H) 4.03-4.15 (m, 4 H) 6.99 (s, 1 H) 7.45-7.53 (m, 2 H) 7.56 (dd, J =8.71, 1.66 Hz, 1 H) 8.11 (d, J = 8.50 Hz, 1 H) 8.90 (s, 1 H) Mass found:342.04 (M + 1) B  2B

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.45 (s, 3 H) 2.75 (s, 3 H) 4.03 (d, J =3.32 Hz, 2 H) 7.00 (s, 1 H) 7.44-7.53 (m, 2 H) 7.56 (dd, J = 8.71, 1.66Hz, 1 H) 8.11 (d, J = 8.71 Hz, 1 H) 8.88 (s, 1 H) 12.94 (br. s., 1 H)Mass found: 314.04 (M + 1) C  3A

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.93 (m, 2 H) 1.11-1.22 (m, 5 H)2.54-2.61 (m, 2 H) 2.70- 2.79 (m, 2 H) 3.14-3.23 (m, 2 H) 3.98-4.08 (m,2 H) 7.46 (d, J = 7.26 Hz, 1 H) 7.56 (d, J = 7.88 Hz, 1 H) 7.69 (td, J =7.62, 1.14 Hz, 1 H) 7.74-7.82 (m, 2 H) 8.27 (br. s., 2 H) 8.60 (d, J =8.50 Hz, 1 H) Mass found: 383.07 (M + 1) B  3B

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.92 (m, 2 H) 1.07-1.23 (m, 5 H)2.54-2.62 (m, 1 H) 2.77 (t, J = 6.84 Hz, 2 H) 3.28 (td, J = 6.89, 2.38Hz, 2 H) 4.03 (q, J = 7.05 Hz, 2 H) 7.15 (d, J = 8.09 Hz, 1 H) 7.44 (d,J = 7.46 Hz, 1 H) 7.62-7.71 (m, 2 H) 7.75 (ddd, J = 8.40, 6.95, 1.24 Hz,1 H) 8.59 (d, 1 H) Mass found: 445.98 (M + 1) B  3D

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88- 0.94 (m, 2 H) 1.18-1.24 (m, 5H) 1.61 (s, 3 H) 1.66 (s, 3 H) 2.42-2.52 (m, 1 H) 4.06-4.14 (m, 2 H)7.15 (d, J = 8.29 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.40 (dd, J = 7.67, 0.83Hz, 1 H) 7.59 (ddd, J = 8.29, 6.95, 1.14 Hz, 1 H) 7.69 (ddd, J = 8.40,6.95, 1.24 Hz, 1 H) 8.58 (d, J = 8.50 Hz, 1 H) Mass found: 460.04(M + 1) A  3E

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-1.00 (m, 2 H) 1.13-1.23 (m, 2 H)1.50 (s, 3 H) 1.54 (s, 3 H) 2.55-2.65 (m, 1 H) 7.05 (d, J = 8.09 Hz, 1H) 7.45 (d, J = 7.67 Hz, 1 H) 7.59 (d, J = 7.46 Hz, 1 H) 7.67 (ddd, J =8.34, 7.00, 1.04 Hz, 1 H) 7.76 (ddd, J = 8.40, 7.05, 1.14 Hz, 1 H) 8.60(d, J = 8.50 Hz, 1 H) 12.97-13.15 (m, 1 H) Mass found: 432.00 (M + 1) A 4A

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J = 7.15 Hz, 3 H) 1.37-1.45 (m,3 H) 3.23 (q, J = 7.46 Hz, 2 H) 4.08-4.18 (m, 4 H) 7.06-7.36 (m, 2 H)7.60-7.76 (m, 4 H) 8.30 (d, 1 H) Mass found: 392.05 (M + 1) C  4B

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (t, J = 7.57 Hz, 3 H) 3.23 (q, J =7.60 Hz, 2 H) 4.09 (s, 2 H) 7.07- 7.36 (m, 2 H) 7.53-7.80 (m, 4 H) 8.29(d, J = 8.29 Hz, 1 H) 13.03 (br. s., 1 H) Mass found: 364.04 (M + 1) B 5A

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.82- 0.96 (m, 2 H) 1.10 (t, J =7.15 Hz, 3 H) 1.21 (dq, J = 8.47, 1.67 Hz, 2 H) 1.50 (s, 3 H) 1.53 (s, 3H) 2.41- 2.50 (m, 1 H) 3.90 (q, J = 7.26 Hz, 2 H) 4.30 (s, 2 H)7.31-7.44 (m, 3 H) 7.60 (ddd, J = 8.34, 7.00, 1.24 Hz, 1 H) 7,69 (ddd, J= 8.40, 6.95, 1.24 Hz, 1 H) 8.57 (d, J = 8.29 Hz, 1 H) Mass found:397.11 (M + 1) C  5B

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.96 (m, 2 H) 1.12-1.21 (m, 2 H)1.33 (s, 3 H) 1.38 (s, 3 H) 2.56-2.60 (m, 1 H) 5.84 (s, 2 H) 7.04 (d, J= 8.29 Hz, 1 H) 7.35-7.45 (m, 2 H) 7.58-7.65 (m, 1 H) 7.67-7.74 (m, 1 H)8.56 (d, J = 8.29 Hz, 1 H) 12.80 (br. s., 1 H) Mass found: 369.10(M + 1) C  6A

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, 3 H) 1.59-1.71 (m, 2 H)1.72-1.84 (m, 2 H) 2.08-2.19 (m, 1 H) 2.24-2.36 (m, 4 H) 2.65-2.72 (m, 2H) 4.08- 4.21 (m, 4 H) 5.23 (d, J = 1.45 Hz, 1 H) 5.35 (d, J = 1.24 Hz,1 H) 7.11 (d, J = 7.88 Hz, 1 H) 7.25 (d, J = 7.88 Hz, 1 H) Mass found:364.11 (M + 1) B  7

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88- 0.94 (m, 2 H) 1.17-1.24 (m, 2H) 1.44 (s, 9 H) 1,61 (s, 3 H) 1.65 (s, 3 H) 2.42-2.51 (m, 1 H) 7.17 (d,J = 7.88 Hz, 1 H) 7.28-7.42 (m, 2 H) 7.58 (ddd, J = 8.29, 6.95, 1.14 Hz,1 H) 7.68 (ddd, J = 8.40, 6.95, 1.24 Hz, 1 H) 8.57 (d, J = 8.29 Hz, 1 H)Mass found: 488.05 (M + 1) C  8

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-0.91 (m, 2 H) 1.12-1.19 (m, 2 H)2.54-2.61 (m, 1 H) 3.99 (d, J = 1.45 Hz, 2 H) 7.16 (d, J = 7.88 Hz, 1 H)7.44 (d, J = 7.46 Hz, 1 H) 7.59-7.70 (m, 2 H) 7.75 (td, J = 7.62, 1.14Hz, 1 H) 8.59 (d, J = 8.50 Hz, 1 H) 12.94 (br. s., 1 H) Mass found:404.5 (M + 1) B  9A

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.93 (m, 2 H) 1.15-1.21 (m, 2 H)1.60 (s, 3 H) 1.62 (s, 3 H) 2.55-2.64 (m, 1 H) 7.09 (d, J = 8.09 Hz, 1H) 7.44 (d, J = 7.05 Hz, 1 H) 7.63-7.73 (m, 2 H) 7.73-7.79 (m, 1 H) 8.60(d, J = 8.29 Hz, 1 H) 13.17 (br. s., 1 H) Mass found: 422.10 (M + 1) A10A

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88- 0.95 (m, 2 H) 1.18-1.27 (m, 5H) 1.95-2.20 (m, 2 H) 2.25-2.42 (m, 2 H) 2.43-2.52 (m, 1 H) 2.75-2.87(m, 2 H) 4.11-4.18 (m, 2 H) 7.21 (d, J = 8.09 Hz, 1 H) 7.33-7.38 (m, 1H) 7.38-7.43 (m, 1 H) 7.61 (ddd, J = 8.29, 6.95, 1.14 Hz, 1 H) 7.70(ddd, J = 8.40, 7.05, 1.14 Hz, 1 H) 8.58 (d, J = 8.29 Hz, 1 H) Massfound: 472.03 (M + 1) N/A 10B

¹H NMR (400 MHz, MeOD) δ ppm 0.86-0.94 (m, 2 H) 1.17-1.27 (m, 5 H)1.92-2.04 (m, 1 H) 2.05-2.15 (m, 1 H) 2.15-2.26 (m, 1 H) 2.31-2.42 (m, 1H) 2.55 (tt, J = 8.37, 5.42 Hz, 1 H) 2.69-2.81 (m, 2 H) 3.64 (q, J =7.05 Hz, 2 H) 7.14 (d, J = 8.09 Hz, 1 H) 7.45-7.52 (m, 2 H) 7.64 (ddd, J= 8.34, 7.00, 1.24 Hz, 1 H) 7.73 (ddd, J = 8.40, 6.95, 1.24 Hz, 1 H)8.65 (d, J = 8.50 Hz, 1 H) Mass found: 444.02 (M + 1) N/A 23

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55-1.86 (m, 4 H) 2,28 (s, 3 H) 2.67(t, J = 6.32 Hz, 2 H) 4.01 (d, J = 5.80 Hz, 2 H) 7.07 (d, J = 7.88 Hz, 1H) 7.20 (d, J = 8.09 Hz, 1 H) 8.70 (s, 1 H) 12.92 (br. s., 1 H) Massfound: 305.05 (M + 1) B 25

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (t, J = 7.05 Hz, 3 H) 1.53-1.80 (m,4 H) 1.89 (s, 3 H) 2.11-2.21 (m, 2 H) 2.24 (s, 3 H) 2.59-2.65 (m, 2 H)4.06-4.19 (m, 4 H) 7.11 (s, 1 H) 8.65 (s, 1 H) Mass found: 346.09(M + 1) B 26

1H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (t, J = 7.15 Hz, 3 H) 1.66 (br. s.,2 H) 1.72-1.86 (m, 2 H) 2.28 (s, 3 H) 2.67 (t, J = 6.22 Hz, 2 H) 3.99-4.18 (m, 4 H) 7.07 (d, J = 7.88 Hz, 1 H) 7.20 (d, J = 7.88 Hz, 1 H) 8.70(s, 1 H) Mass found: 332.12 (M + 1) B 27

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.78 (m, 4 H) 1.89 (s, 3 H) 2.17(t, J = 6.12 Hz, 2 H) 2.24 (s, 3 H) 2.58-2.65 (m, 2 H) 4.06 (s, 2 H)7.11 (s, 1 H) 8.64 (s, 1 H) 12.92 (br. s., 1 H) Mass found: 318.08(M + 1) C 28

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.82 (m, 4 H) 2.22-2.30 (m, 5 H)2.67 (t, J = 6.32 Hz, 2 H) 4.01 (d, J = 5.80 Hz, 2 H) 7.07 (d, J = 7.88Hz, 1 H) 7.20 (d, J = 8.09 Hz, 1 H) 8.70 (s, 1 H) 12.92 (br. s., 1 H)Mass found: 304.05 (M + 1) C 31

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.02 (s, 3 H) 3.52 (m, 2 H) 7.60-7.92(m, 3 H) 8.22 (d, 1 H) 8.56 (d, 1 H) 8.84 (d, 1 H) Mass found: 301.10(M + 1) C 32

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92 (br. s., 2 H) 2.18 (s, 3 H)2.25-2.37 (m, 6 H) 7.15 (d, J = 7.26 Hz, 1 H) 7.22 (br. s., 1 H) 7.35(d, J = 6.84 Hz, 1 H) Mass found: 278.07 (M + 1) C 33

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92 (s, 2 H) 2.15 (s, 3 H) 7.58-7.72(m, 3 H) 7.78-7.84 (m, 1 H) Mass found: 284.00 (M + 1) C 36

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.94 (br. s., 3 H) 2.07 (s, 3 H) 2.38(s, 3 H) 7.14-7.24 (m, 2 H) 7.30 (s, 1 H) Mass found: 278.07 (M + 1) C37

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (s, 3 H) 3.57 (d, J = 3.11 Hz, 2 H)3.80 (s, 3 H) 7.13 (td, J = 7.62, 1.14 Hz, 1 H) 7.30 (d, J = 8.29 Hz, 1H) 7.35 (dd, J = 7.67, 1.66 Hz, 1 H) 7.54-7.60 (m, 1 H) Mass found:280.02 (M + 1) C 38

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.93 (s, 6 H) 2.05 (s, 3 H) 3.70 (br.s., 2 H) 7.28-7.34 (m, 2 H) 7.36- 7.42 (m, 1 H) Mass found: 278.07(M + 1) C 46

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.95 (m, 2 H) 1.12-1.24 (m, 5 H)2.54-2.64 (m, 1 H) 4.01 (d, J = 1.45 Hz, 2 H) 4.07-4.17 (m, 2 H) 7.48(d, J = 7.67 Hz, 1 H) 7.53 (d, J = 7.88 Hz, 1 H) 7.72 (td, J = 7.62,1.14 Hz, 1 H) 7.76-7.83 (m, 2 H) 8.34 (br. s., 2 H) 8.62 (d, J = 8.29Hz, 1 H) Mass found: 369.10 (M + 1) C 47

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.92 (m, 2 H) 1.16 (dd, J = 8.50,2.07 Hz, 2 H) 2.54-2.59 (m, 1 H) 3.71 (s, 2 H) 5.75 (s, 2 H) 7.23 (d, J= 8.09 Hz, 1 H) 7.38-7.44 (m, 1 H) 7.46-7.52 (m, 1 H) 7.60-7.67 (m, 1 H)7.72 (ddd, J = 8.40, 6.95, 1.24 Hz, 1 H) 8.56 (d, J = 8.50 Hz, 1 H) Massfound: 341.03 (M + 1) B 48

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.96 (m, 2 H) 1.08-1.24 (m, 5 H)1.39-1.49 (m, 3 H) 2.56- 2.64 (m, 1 H) 4.00-4.13 (m, 2 H) 4.22 (dq, J =16.35, 7.20 Hz, 1 H) 7.44-7.56 (m, 2 H) 7.66-7.82 (m, 3 H) 8.26 (br. s.,2 H) 8.62 (d, J = 8.50 Hz, 1 H) Mass found: 383.07 (M + 1) B 49

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.93 (m, 2 H) 1.14-1.22 (m, 2 H)1.35 (t, J = 7.46 Hz, 3 H) 2.55- 2.62 (m, 1 H) 3.83-3.99 (m, 1 H) 6.39(br, s., 2 H) 7.25 (t, J = 7,57 Hz, 1 H) 7.43 (d, J = 7.67 Hz, 1 H) 7.55(dd, J = 7.67, 2.28 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.70- 7.77 (m, 1 H) 8.58(d, J = 8.50 Hz, 1 H) Mass found: 355.07 (M + 1) B 51

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (t, 3 H) 3.20 (q, 2 H) 4.03(m, 2 H) 5.01-5.43 (m, 2 H) 7.07-7.65 (m, 4 H) 8.02-8.22 (m, 2 H) Massfound: 346.0 (M + 1) B 53

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.75 (s, 3 H) 4.02 (s, 2 H) 6.95-7.38(m, 1 H) 7.50-8.21 (m, 5 H) Mass found: 350.0 (M + 1) B 54

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.50-1.82 (m, 4 H) 2.18-2.35 (m, 4 H)2.64 (s, 3 H) 7.02-7.71 (m, 4 H) Mass found: 353.1 (M + 1) B 56

¹H NMR (400 MHz, MeOD) δ ppm 0.85-0.94 (m, 2 H) 1.16-1.26 (m, 2 H) 2.02(s, 1 H) 2.48-2.59 (m, 1 H) 4.06 (br. s., 2 H) 6.70-7.03 (m, 1 H) 7.22(d, J = 8.29 Hz, 1 H) 7.45 (d, J = 7.46 Hz, 1 H) 7.54-7.66 (m, 2 H)7.68-7.75 (m, 1 H) 8.63 (d, J = 8.50 Hz, 1 H) Mass found: 376.06 (M + 1)B 61

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, 3 H) 2.16 (s, 3 H) 2.77 (s, 3H) 4.10-4.26 (m, 4 H) 7.00 (d, J = 7.88 Hz, 1 H) 7.08-7.38 (m, 1 H) 7.54(s, 1 H) 7.58- 7.72 (m, 2 H) 8.14-8.20 (m, 1 H) Mass found: 392.05(M + 1) C 62

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15 (s, 3 H) 2.76 (s, 3 H) 4.02-4.20(m, 2 H) 7.00 (d, J = 7.88 Hz, 1 H) 7.09-7.37 (m, 1 H) 7.54 (s, 1 H)7.58-7.71 (m, 2 H) 8.16 (d, J = 7.67 Hz, 1 H) 13.03 (br. s., 1 H) Massfound: 364.04 (M + 1) B 64

¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.04 (s, 2 H) 7.19 (d, 1 H) 6.95-7.38(m, 1 H) 7.50-8.21 (m, 5 H) Mass found: 353.9 (M + 1) B 66

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.25 (m, 3 H) 1.60-1.72 (m, 2 H)1.78 (quin, J = 6.12 Hz, 2 H) 2.05-2.16 (m, 1 H) 2.28-2.40 (m, 4 H) 2.69(t, J = 6.32 Hz, 2 H) 4.12-4.29 (m, 4 H) 7.22-7.30 (m, 2 H) Mass found:400.08 (M + 1) B 67

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.72 (m, 2 H) 1.78 (quin, J = 6.01Hz, 2 H) 2.10 (dt, J = 16.74, 5.93 Hz, 1 H) 2.26-2.40 (m, 4 H) 2.69 (t,J = 6.22 Hz, 2 H) 4.08-4.23 (m, 2 H) 7.21-7.29 (m, 2 H) 13.09 (br. s., 1H) Mass found: 372.01 (M + 1) A 69

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-0.91 (m, 2 H) 1.12-1.19 (m, 2 H)2.53-2.61 (m, 1 H) 3.64 (s, 3 H) 4.06 (d, J = 3.73 Hz, 2 H) 7.15 (d, J =8.09 Hz, 1 H) 7.45 (d, J = 7.67 Hz, 1 H) 7.61-7.71 (m, 2 H) 7.75 (td, J= 7.62, 1.14 Hz, 1 H) 8.59 (d, J = 8.29 Hz, 1 H) Mass found: 418.2(M + 1) B 70

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.78 (s, 3 H) 3.84 (s, 2 H) 7.12 (d, 1H) 7.52-7.78 (m, 4 H) 8.21 (d, 2 H) Mass found: 377.8 (M + 1) B 73

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (t, J = 7.46 Hz, 3 H) 3.24 (q,J = 7.60 Hz, 2 H) 3.76 (s, 3 H) 4.08 (d, J = 6.43 Hz, 2 H) 7.25-7.28 (m,1 H) 7.39- 7.44 (m, 1 H) 7.50 (d, J = 7.46 Hz, 1 H) 7.60 (ddd, J = 8.29,6.95, 1.14 Hz, 1 H) 7.64-7.70 (m, 1 H) 8.21 (d, J = 8.29 Hz, 1 H) Massfound: 405.95 (M + 1) A 74

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (t, J = 7.57 Hz, 3 H) 3.22 (q, J =7.46 Hz, 2 H) 4.01 (d, J = 1.66 Hz, 2 H) 7.17 (d, J = 8.09 Hz, 1 H)7.58-7.77 (m, 4 H) 8.30 (d, J = 8.50 Hz, 1 H) Mass found: 391.92 (M + 1)A 76

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.93 (m, 2 H) 1.10-1.24 (m, 5 H)2.58 (tt, J = 8.42, 5.47 Hz, 1 H) 3.98-4.16 (m, 4 H) 7.17 (d, J = 8.09Hz, 1 H) 7.46 (d, J = 7.46 Hz, 1 H) 7.62-7.72 (m, 2 H) 7.77 (ddd, J =8.34, 7.00, 1.24 Hz, 1 H) 8.61 (d, J = 8.29 Hz, 1 H) Mass found: 431.96(M + 1) A 78

¹H NMR (400 MHz, MeOD) δ ppm 0.83-0.91 (m, 2 H) 1.16-1.24 (m, 2 H) 2.02(s, 2 H) 2.43-2.55 (m, 1 H) 3.83 (s, 3 H) 6.47 (d, J = 2.49 Hz, 1 H)7.29 (d, J = 7.67 Hz, 1 H) 7.35 (dd, J = 9.33, 2.49 Hz, 1 H) 7.48 (d, J= 7.67 Hz, 1 H) 8.53 (d, J = 9.33 Hz, 1 H) Mass found: 433.96 (M + 1) B82

¹H NMR (400 MHz, MeOD) δ ppm 1.45 (t, J = 7.46 Hz, 3 H) 3.22 (q, J =7.60 Hz, 2 H) 3.83 (s, 3 H) 3.89-4.14 (m, 2 H) 6.49 (d, J = 2.49 Hz, 1H) 7.33 (dd, J = 9.33, 2.49 Hz, 1 H) 7.38-7.46 (m, 1 H) 7.47-7.54 (m, 1H) 8.20 (d, J = 9.33 Hz, 1 H) Mass found: 421.95 (M + 1) B 85

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85- 0.96 (m, 2 H) 1.16-1.31 (m, 5H) 1.54-1.71 (m, 3 H) 2.47 (tt, J = 8.50, 5.49 Hz, 1 H) 4.09-4.23 (m, 2H) 4.53 (qd, J = 7.22, 4.66 Hz, 1 H) 7.24 (t, J = 7.15 Hz, 1 H)7.32-7.43 (m, 2 H) 7.57-7.65 (m, 1 H) 7.66-7.74 (m, 1 H) 8.54-8.61 (m, 1H) Mass found: 446.00 (M + 1) B 86

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88- 0.96 (m, 2 H) 1.19-1.26 (m, 2H) 1.51-1.62 (m, 3 H) 2.48 (tt, J = 8.47, 5.42 Hz, 1 H) 4.35 (dq, J =14.67, 7.27 Hz, 1 H) 7.23 (dd, J = 11.20, 8.29 Hz, 1 H) 7.35-7.44 (m, 2H) 7.64 (m, J = 8.40, 6.95, 1.45, 1.45 Hz, 1 H) 7.69-7.77 (m, 1 H) 8.60(dd, J = 8.29, 5.60 Hz, 1 H) Mass found: 417.97 (M + 1) A 88

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87-0.94 (m, 2 H) 1.15-1.21 (m, 2 H)1.41 (s, 9 H) 2.55-2.63 (m, 1 H) 3.93 (d, J = 2.70 Hz, 2 H) 7.18 (d, J =8.09 Hz, 1 H) 7.47 (d, J = 7.67 Hz, 1 H) 7.66 (d, J = 7.67 Hz, 1 H)7.68- 7.72 (m, 1 H) 7.78 (ddd, J = 8.40, 6.95, 1.24 Hz, 1 H) 8.62 (d, J= 8.50 Hz, 1 H) Mass found: 460.01 (M + 1) C 89

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J = 7.15 Hz, 3 H) 1.50 (t,J = 7.46 Hz, 3 H) 1.62 (s, 3 H) 1.66 (s, 3 H) 3.25 (q, J = 7.53 Hz, 2 H)4.06-4.14 (m, 2 H) 7.16 (d, J = 8.50 Hz, 1 H) 7.36 (d, J = 7.67 Hz, 1 H)7.50 (d, J = 7.46 Hz, 1 H) 7.57 (ddd, J = 8.34, 7.00, 1.04 Hz, 1 H) 7.66(ddd, J = 8.45, 7.00, 1.35 Hz, 1 H) 8.21 (d, J = 8.50 Hz, 1 H) Massfound: 448.02 (M + 1) A 90

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.44 (m, 3 H) 1.50 (s, 3 H) 1.54(s, 3 H) 3.22 (qd, J = 7.43, 4.04 Hz, 2 H) 7.04 (d, J = 7.67 Hz, 1 H)7.58-7.67 (m, 3 H) 7.68-7.75 (m, 1 H) 8.29 (d, J = 8.29 Hz, 1 H) 13.09(br. s., 1 H) Mass found: 419.99 (M + 1) A

Example 13 In Vitro Metabolic Stability

In vitro metabolic stability was assessed in rat and human livermicrosomes (RLM/HLM). The incubation mixer contained the following: 1 uMtest compound, 1 mg/mL HLM/RLM, 100 mM potassium phosphate buffer at pH7.4, 1 mM NADPH and 5 mM MgCl₂. This mixture was preincubated for 3 minbefore the 30 minute incubation at 37° C. The reaction was initiatedwith the addition of NADPH and terminated by the addition of equalvolume of acetonitrile with internal standard. Incubation sampleswithout NADPH were used as control samples. After vortexing andcentrifugation, the supernatant was injected onto LC-MS/MS forquantitation.

The compound prepared in example 3E above,(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoicacid) was examined according to this procedure and the results shown inthe table below.

Liver Microsome Stability Compound % Remaining Example 3E Human Rat

97 ± 2% 98 ± 0.1%

Example 14 Methyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

1-Cyclopropylnaphthalene

Cyclopropylmagnesium bromide (150 mL, 0.5M in tetrahydrofuran) wasslowly added to a solution of 1-bromonaphthalene (10 g, 50 mmol) and[1,3-bis(diphenylphosphino)propane]dichloro nickel (II) intetrahydrofuran (10 mL) stirred at 0° C., and the reaction mixturestirred at room temperature for 16 hours. The solvent was removed underreduced pressure and ethyl acetate and aqueous ammonium chloride wereadded. After extraction, the organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to yield1-cyclopropylnaphthalene (6.4 g, 76%).

1-Cyclopropyl-4-nitronaphthalene

Sodium nitrite (30 mL) was slowly added (over 2 hours) to1-cyclopropylnaphthalene (6.4 g, 38 mmol) stirred at 0° C. The reactionmixture was stirred at 0° C. for an extra 30 min and then slowly pouredinto ice. Water was added, followed by ethyl acetate. After extraction,the organic layer was washed with aqueous sodium hydroxide (1%) andwater, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto yield 1-cyclopropyl-4-nitronaphthalene (5.2 g, 64%).

1-Amino-4-cyclopropylnaphthalene

A solution of 1-cyclopropyl-4-nitronaphthalene (5 g, 23 mmol) in ethanol(200 mL) was stirred under hydrogen in the presence of Pd/C (10% net,10.8 g). The reaction mixture was shaken overnight, filtered overcelite, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to yield1-amino-4-cyclopropylnaphthalene (3.1 g, 73%).

1-Cyclopropyl-4-isothiocvanatonaphthalene

Thiophosgene (1.1 g, 9.7 mmol) was added to a stirred solution of1-amino-4-cyclopropylnaphthalene (1.8 g, 9.7 mmol) anddiisopropylethylamine (2 eq) in dichloromethane (50 mL) at 0° C. Thereaction mixture was stirred for 5 min at 0° C. and then aqueous HCl (1%solution) was added. The organic layer was separated, washed with brine,dried over sodium sulfate, filtered and the solvent removed underreduced pressure. Hexane was added, and the resulting precipitate wasfiltered. The solvent was evaporated to yield1-cyclopropyl-4-isothiocyanatonaphthalene (1.88 g, 86%).

5-Amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol

A mixture of aminoguanidine hydrochloride (3.18 g, 29 mmol),1-cyclopropyl-4-isothiocyanatonaphthalene (3.24 g, 14 mmol) anddiisopropylethylamine (3 eq) in DMF (20 mL) was stirred at 50° C. for 15hours. The solvent was removed under reduced pressure, toluene added,and the solvent was evaporated again. Sodium hydroxide solution (2M, 30mL) was added and the reaction mixture heated at 50° C. for 60 hours.The reaction mixture was filtered and the filtrate neutralized withaqueous HCl (2M). The mixture was re-filtered and the solvent removedunder reduced pressure. The residue was purified by silica gelchromatography to yield5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.0g, 49%).

Methyl2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Methyl 2-chloroacetate (0.73 mL, 8.3 mmol) was added dropwise over 5mins to a suspension of5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.24g, 7.9 mmol) and potassium carbonate (1.21 g, 8.7 mmol) in DMF (40 mL)at room temperature. The reaction was stirred at room temperature for 24h and slowly poured into a stirred ice-cold water solution. The tanprecipitate was collected by vacuum filtration and dried under highvacuum at 50° C. for 16 h in the presence of P₂O₅ to yield methyl2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate(2.24 g, 80%).

Methyl2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Sodium nitrite (2.76 g, 40 mmol) was added to a solution of methyl2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate(0.71 g, 2 mmol) and benzyltriethylammonium chloride (1.63 g, 6 mmol) inbromoform (110 mL). Dichloroacetic acid (0.33 mL, 4 mmol) was then addedand the reaction mixture stirred at room temperature for 3 h. Themixture was directly loaded onto a 7-inch column of silica gel, packedwith dichloromethane (DCM). The column was first eluted with DCM untilall bromoform eluted, then eluted with acetone/DCM (5:95) to give methyl2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate(713 mg, 85%).

Example 152-(5-Bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticAcid

A solution of lithium hydroxide (95 mg, 4.1 mmol) in water (10 mL) wasadded dropwise over 5 mins to a solution of methyl2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate(prepared as described in example 1 above; 1.14 g, 2.7 mmol) in ethanol(10 mL) and THF (10 mL) at 0° C. The mixture was stirred at 0° C. for afurther 45 mins and then neutralized to pH 7 by the addition of 0.5N HClsolution at 0° C. The resulting mixture was concentrated in vacuo to ⅕thof its original volume, then diluted with water (˜20 mL) and acidifiedto pH 2-3 by the addition of 0.5N HCl to produce a sticky solid. (If theproduct comes out as an oil during acidification, extraction with DCM isrecommended.) The tan solid was collected by vacuum filtration and driedunder high vacuum at 50° C. for 16 h in the presence of P₂O₅ to yield2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (1.02 g, 93%).

Example 16 Sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Aqueous sodium hydroxide solution (1M, 2.0 mL, 2.0 mmol) was addeddropwise over 5 mins to a solution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (810 mg, 2.0 mmol) in ethanol (10 mL) at 10° C. The mixture wasstirred at 10° C. for a further 10 mins. Volatile solvents were removedin vacuo to dryness to provide sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateas a solid (850 mg, 100%).

Example 17 Potassium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Aqueous potassium hydroxide solution (1M, 2.0 mL, 2.0 mmol) was addeddropwise over 5 mins to a solution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (810 mg, 2.0 mmol) in ethanol (10 mL) at 10° C. The mixture wasstirred at 10° C. for a further 10 mins. Volatile solvents were removedin vacuo to dryness to provide potassium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateas a solid, (884 mg, 100%).

Example 182-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-hydroxyacetamide

A solution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (10 mmol) in THF (2 mL) and methanol (2 mL) is added to a solutionof sodium hydroxide (5 mmol) and 50% aqueous hydroxylamine (2 mL). Afterstirring for 1 hr at room temperature, water (4 mL) is added and thevolatile solvents removed in vacuo. The solution is then neutralized topH 7-8 by addition of HCl (1N), and the resulting precipitate isolatedby filtration to provide2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-hydroxyacetamide.

Example 192-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-N(R^(4a),R^(4b))-acetamide

Phosphorus oxychloride (20.6 mmol) is added dropwise over 5 mins to asolution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (2.2 mmol) and amine (NHR^(4a)R^(4b); 2.2 mmol) in pyridine (22 mL)at 0° C. The mixture is stirred at 0° C. for a further 1 hour and thenquenched by addition of water (1 mL). Volatile solvents are removed invacuo and DCM (200 mL) added. The organic phase is washed with water(1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50mL), dried over Na₂SO₄ and concentrated to dryness. Ethanol and waterare added to produce a solid which is collected by filtration.Additional product is recovered by extraction of the filtrate with DCM.The combined product is concentrated, dried and purified by columnchromatography (acetone/DCM eluent) to provide2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-N(R^(4a),R^(4b))-acetamide.

Example 202-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)aceticAcid

Glycine ethyl ester hydrochloride (0.21 g, 1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g,1.86 mmol), 1-hydroxy-7-azabenzotriazole (0.25 g, 1.86 mmol) and2,6-lutidine (0.43 mL, 3.71 mmol, 3.0) are added to a solution of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL), and the mixture isstirred at room temperature for 18 hours. Purification by SGC (0-100%EtOAc/Hexanes) affords2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)aceticacid.

Example 212-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)aceticAcid

Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to asolution of ethyl2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetate(0.4 mmol) in 3:1, THF/H₂O (1.6 mL) and the mixture stirred for 18 h atroom temperature. The crude reaction mixture is concentrated andacidified with aqueous HCl (1M, 1.2 mL) and then is extracted with ethylacetate (3×3 mL). The combined organic extracts are dried (sodiumsulfate), filtered and concentrated to provide2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)aceticacid.

Example 22 Methyl2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)propanoate

Alanine methyl ester hydrochloride (1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol),1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71mmol) are added to a solution of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture isstirred at room temperature for 18 hours and then purified by SGC(0-100% EtOAc/Hexanes).

Example 232-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)propanoicAcid

Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to asolution of methyl2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)propanoate(0.4 mmol) in 3:1, THF/H₂O (1.6 mL) and the mixture stirred for 18 h atroom temperature. The crude reaction mixture is concentrated andacidified with aqueous HCL (1M, 1.2 mL) and then is extracted with ethylacetate (3×3 mL). The combined organic extracts are dried (sodiumsulfate), filtered and concentrated to provide the desired product.

Example 24 Methyl2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-phenylpropanoate

Phenylalanine methyl ester hydrochloride (1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol),1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71mmol) are added to a solution of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture isstirred at room temperature for 18 hours and then purified by SGC(0-100% EtOAc/Hexanes).

Example 252-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-phenylpropanoicAcid

Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to asolution of methyl2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-phenylpropanoate(0.4 mmol) in 3:1, THF/H₂O (1.6 mL) and the mixture stirred for 18 h atroom temperature. The crude reaction mixture is concentrated andacidified with aqueous HCL (1M, 1.2 mL) and then is extracted with ethylacetate (3×3 mL). The combined organic extracts are dried (sodiumsulfate), filtered and concentrated to provide the desired product.

Example 26 Methyl2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(2-(5-bromo-4-(4cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)hexanoate

Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-aminohexanoate(N-α-Fmoc-Lysine (NH₂)—OMe, 1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol),1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71mmol) are added to a solution of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture isstirred at room temperature for 18 hours and then is purified by SGC(0-100% EtOAc/Hexanes).

Example 27 2-(1,2-Dihydroxyethyl)-4,5-dihydroxytetrahydrofuran-3-yl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to asolution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture isstirred at 0° C. for a further 1 hour and then a solution of1,2:5,6-Di-O-isopropilydene-□-D-glucofuranose (320 mg, 2.0 mmol) inpyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at0° C. for a further 1 hour and 1 hour at 20° C. and then is quenched byaddition of water (1 mL). Volatile solvents are removed in vacuo and DCM(200 mL) added. The organic phase is washed with water (1×50 mL),saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), driedover Na₂SO₄ and concentrated to dryness. Ethanol and water are added toproduce a solid which is collected by filtration. Additional product isrecovered by extraction of the filtrate with DCM. Combined product isconcentrated, dried and purified by column chromatography (acetone/DCMeluent). The combined solids are dissolved in acetic acid (25 mL) andwater (5 mL) mixture, heated at 60° C. for 3 hours. Volatile solventsare removed in vacuo. Ethanol and water are added to produce a solidwhich is collected by filtration.

Example 28 2-hydroxy-2-(3,4,5-trihydroxytetrahydrofuran-2-yl)ethyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to asolution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture isstirred at 0° C. for a further 1 hour and then1,2-O-isopropilydene-□-D-glucofuranose (440 mg, 2.0 mmol) dissolved inpyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at0° C. for a further 3 hours and 1 hour at 20° C. and then quenched byaddition of water (1 mL). Volatile solvents are removed in vacuo and DCM(200 mL) added. The organic phase is washed with water (1×50 mL),saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), driedover Na₂SO₄ and concentrated to dryness. Ethanol and water are added toproduce a solid which is collected by filtration. Additional product isrecovered by extraction of the filtrate with DCM. Combined product isconcentrated, dried and purified by column chromatography (acetone/DCMeluent). The combined solids are dissolved in acetic acid (25 mL) andwater (5 mL) mixture, heated at 60° C. for 3 hours. Volatile solventsare removed in vacuo. Ethanol and water are added to produce a solidwhich is collected by filtration.

Example 293-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetoxy)-2-hydroxypropylOleate

Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to asolution of2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture isstirred at 0° C. for a further 1 hour and then glyceryl monooleate (715mg, 20 mmol) dissolved in pyridine (5 mL) is added dropwise over 5 mins.The mixture is stirred at 0° C. for a further 3 hours and 1 hour at 20°C. and then quenched by addition of water (1 mL). Volatile solvents areremoved in vacuo and DCM (200 mL) added. The organic phase is washedwith water (1×50 mL), saturated sodium carbonate solution (1×50 mL) andbrine (1×50 mL), dried over Na₂SO₄, concentrated to dryness and purifiedby column chromatography (acetone/DCM eluent) to provide3-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetoxy)-2-hydroxypropyloleate.

Example 30((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

The title oxyribonucleoside compound is prepared according to thesynthetic scheme shown above. Protecting groups may be employed and mayor may not be removed at the end of the synthesis.

Example 31((2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

The title deoxyribonucleoside compound is prepared according to thesynthetic scheme shown above. Protecting groups may be employed and mayor may not be removed at the end of the synthesis.

Example 32((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl)methyl2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

The title oxyribonucleotide compound is prepared according to thesynthetic scheme shown above. Protecting groups may be employed and mayor may not be removed at the end of the synthesis.

Example 332-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)aceticAcid-PEG Conjugate

The title PEG-conjugate is prepared according to the synthetic schemeshown above. Protecting groups may be employed and may or may not beremoved at the end of the synthesis.

Example 34 Solubility of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate—FreeAcid, Sodium and Piperazine Salts

To 1.00 mL (or 0.50 mL) of test solvent in an eppendorf vial, was addedvarious weighed amounts of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,(as the free acid, sodium and piperazine salts), and the weightsrecorded. When it appeared the saturation point was being reached,addition was stopped, and the eppendorf vial was shaken at a constantspeed of 1000 rpm at 22° C. for 24 hours. The tubes were thencentrifuged for 5 minutes at 10-15,000 rpm, and checked forprecipitation. Samples were diluted with acetonitrile/water, (1/1) (oriso-propyl alcohol for hexane) and analyzed by HPLC against knownstandards. The results are shown in the table below.

Solubility (mg/mL) Solvent Free Acid Na salt Piperazine saltDMSO >122.9 >136 ~54 Acetone 7.9 0.26 Water (pH 4.85) 49.2 PEG-400 1.22.4 IPA >102.1 6.4 1.6 EtOAc 2.1 0.055 Acetonitrile ~47.6Methanol >130.9 Hexane ~18.4 Dichloromethane >215.3 Ethanol 9.1

II Clinical Examples Example 35 In Vivo Uric Acid Lowering Activity

The uric acid lowering activity of the compounds described herein wasdemonstrated in a multiple ascending dose, double-blind,placebo-controlled study in healthy adult male human volunteers, asfollows.

The study was performed in compliance with the current version of thedeclaration of Helsinki and with the ICH note for guidance on goodclinical practice (CPMP/ICH/135/95).

16 healthy male individuals, aged 18-45 years inclusive, with a bodymass index (BMI) within 18-30 kg/m² inclusive, having provided a writteninformed consent, non smokers for at least 6 months, not using any drugtreatment for 2 weeks before screening (2 months for enzyme-inducingdrugs) except occasional Acetaminophen. The individuals were confined atthe clinical site beginning the day before dose administration until 72hours after the final dose administration on Day 17 and returned for afollow-up visit on Day 21±1.

The study was performed using(4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt), supplied as 100-mg solid powder in size 2 gelatincapsules. Matching placebo capsules were supplied as size 2 gelatincapsules. Individuals were randomized to receive the same number ofplacebo capsules as administered to the active individuals.

Capsules (active or placebo) were administered orally with 240 mL water30 min after a standard breakfast (morning dose) and dinner (eveningdose) for 14 days.

16 individuals (8 individuals [6 active and 2 placebo] per dose group).

a. Group 1: Placebo b. Group 2: 300 mg (3 × 100-mg capsules) example 1b.i.d. c. Group 3: 500 mg (5 × 100-mg capsules) example 1 b.i.d.

Blood was collected from the individuals on days 0, 3, 7, 14 and atfollow-up. Serum uric levels were measured using standard automatedprocedures. The results are shown in the table below (uric acid levelsin μmol/L).

Uric Acid Analysis 95% (μmol/L) time-point MEAN C.I.<a> S.E S.D MEDIANMIN MAX Placebo Day 3 14.5726 (−66.36491; 95.51011) 25.43248 50.864969.5168 −39.257 78.514 (n = 4) Day 7 2.0818 (−52.72848; 56.89208)17.22269 34.44537 5.9480 −38.067 34.498 Day 14 14.2752 (−60.30917;88.85957) 23.43618 46.87235 16.3570 −35.093 59.480 Follow up −22.6024(−64.91525; 19.71045) 13.29570 26.59140 −26.7660 −48.179 11.301 300 mgDay 3 −100.3229 (−137.35391; −63.29195) 14.40568 35.28657 −101.4134−137.399 −58.885 (n = 6) Day 7 −126.2959 (−181.13450; −71.45723)21.33316 52.25536 −119.8522 −203.422 −68.402 Day 14 −121.2401(−188.47405; −54.00608) 26.15516 64.06680 −104.9822 −201.637 −60.075Follow up −2.2801 (−81.47624; 76.91610) 30.80866 75.46549 0.8922−114.796 77.919 500 mg Day 3 −118.7617 (−171.20777; −66.31569) 20.4024049.97547 −112.1198 −179.630 −47.584 (n = 6) Day 7 −127.6837 (−172.68132;−82.68615) 17.50482 42.87789 −144.2390 −168.923 −59.480 Day 14 −111.8224(−161.47549; −62.16931) 19.31590 47.31409 −124.9080 −167.139 −33.309Follow up 27.2617 (−24.73034; 79.25368) 20.22578 49.54283 27.3608−54.722 98.142

FIGS. 1 and 2 represent uric acid levels (in mg/dL and μmol/L,respectively) 0, 3, 7 and 14 days after administering example 1 at dosesof 300 mg, 400 mg or 500 mg b.i.d. (twice daily)

FIGS. 3 and 4 represent the change in uric acid levels (in mg/dL and 1mol/L, respectively) 3, 7 and 14 days after administering example 1 atdoses of 300 mg, 400 mg or 500 mg b.i.d. (twice daily).

FIG. 5 represents the change in uric acid levels (μmol/dL) by treatmentday after administering example 1 at doses of 300 mg, 400 mg or 500 mgb.i.d. (twice daily).

Example 36 Human Clinical Trial Comparing Efficacy of4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicAcid Versus Indomethacin

Design

This is a double-blind, parallel-group, multicenter, randomized, 5-daystudy.

Endpoints

The primary efficacy endpoint is:

a. Individual assessment of pain.

The secondary efficacy endpoints are:

a. Tenderness of the study joint;

b. Swelling of the study joint; and

c. Proportion of individuals discontinuation due to lack of efficacy.

Treatment Regime

Individuals are randomized into two groups: a control group (n=100) andan experimental group (n=100).

The control group is administered Indomethacin (75 mg) sustained releasecapsule (2 times daily) for a total of two weeks.

The experimental group is administered4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt supplied as 100-mg solid powder in size 2 gelatincapsules for a total of two weeks.

Inclusion Criteria

Male or female

≧18 years of old

Diagnosed with gout according to the 1980 ARA Criteria for theClassification of Acute Arthritis of Primary Gout.

Experiencing an acute attack of clinically diagnosed gout <48 hoursprior to randomization.

Score a sum of 5 across the 3 symptom questions for pain (O— to 4-Likertscale), tenderness (0- to 3-point scales), and swelling [0- to 3-pointscales] with the pain score being at least moderate (i.e. 2, 3, or 4 onthe 0- to 4-Likert scale).

Female individuals of childbearing potential must have a negativepregnancy test.

Female individuals of childbearing potential must be infertile or oncontraception.

Statistical Methodology

The primary analysis is based on change from baseline in individualassessment of pain computed from the average of responses on Study Days2 through 5 using an intention-to-treat approach. All individualefficacy variables (except endpoints defined as proportions) areassessed by ANCOVA (model to include terms for study site, stratum[monoarticular versus polyarticular acute gout], baseline covariate, andtreatment group), pending no 2-factor interactions with treatment. Thecomparability of treatment groups is assessed by 95% confidenceintervals for pairwise treatment difference. The 95% confidence intervalfor individual assessment of pain must fall entirely within thecomparability bounds (i.e., ±0.5 Likert units). Endpoints defined asproportions are compared between groups using Fisher's exact test.Assumptions of normality and homogeneity are assessed by theShapiro-Wilk statistic and Levene's test, respectively. If a significantinteraction (pδ0.050) is found, then the nature of the interaction isassessed and further exploratory analyses is performed.

Example 37 Human Clinical Trial Comparing Efficacy of4-(2-(5-bromo-4-(4-cyclopropyadaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicAcid in Individuals Treated for Hypertension

Hypothesis

Thiazide-induced hyperuricemia decreases the efficacy of thiazides incontrolling BP, leads to endothelial dysfunction, and increases theincidence of insulin resistance and impaired glucose tolerance.

Study Design

This study is a randomized, double-blind, placebo-controlled clinicaltrial of 8-week duration in which a total of 220 African Americanindividuals with untreated stage I hypertension will be enrolled,randomized, and treated as follows:

The experimental group receives chlorthalidone (25 mg/day) and potassiumchloride (40 mEq/day) for 4 weeks. They are then randomized to add-on acompound of4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt (300 mg/day) or placebo.

The dosage of4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid will be adjusted to achieve serum uric acid levels between 4 and5.5 mg/dL. All individuals will receive a low-sodium diet.

Endpoints

The primary endpoint is reduction in systolic BP.

The secondary endpoints measure changes in endothelial function,ambulatory blood pressure, body composition, systemic inflammation,metabolic parameters, oxidant stress, and renal hemodynamics.

Inclusion Criteria:

African American (including black individuals born in the Caribbean,Africa, Canada, etc.)

Male or female

18 years of age or older

Untreated with any antihypertensive agent, with an average sittingclinic BP of between 140/90 and 159/99 mm Hg

Random spot urine protein/creatinine ratio of less than 0.5(approximates a 24-hour urinary protein excretion of 500 mg/day)

Calculated MDRD GFR of greater than or equal to 60 ml/min/1.73/m̂2

No allopurinol or probenecid intake for at least one month prior tostudy entry

Exclusion Criteria

History of cancer or accelerated hypertension

Confirmed total white cell count of less than 2,500/mm̂3, anemia, orthrombocytopenia

Known history of liver disease

Known secondary cause of hypertension

Known presence of diabetes or fasting blood glucose greater than orequal to 126 mg/dL

History of heart failure, acute myocardial infarction, or stroke or on aβ-blocker or calcium channel blocker for cardiovascular indicationsother than for lowering blood pressure

Abnormal EKG requiring medical intervention

History of clinical or renal biopsy or evidence of renal parenchymaldisease

Acute gout attack within 2 weeks of study entry

History of drug abuse in the last 2 years, including narcotics, cocaine,or alcohol (greater than 21 drinks/week)

Arm circumference of greater than 52 cm, which precludes measurementwith a ‘thigh’ BP cuff

Pregnant or planning to become pregnant during the study, orbreastfeeding

History of noncompliance, are unable to comply with the studyrequirements, or who are currently participating in another study

Not fasting prior to obtaining screening laboratory data. If aparticipant has clearly not fasted, we will exclude those individualswith casual blood glucose levels of greater than or equal to 200 mg/dL.In the event that a fasting blood sugar exceeds 126 mg/dL, it will bereconfirmed on a blood glucose measurement obtained on a subsequent day,per American Diabetes Association criteria

Example 38 Human Clinical Trial for Hyperuricemia or Hyperuricosuria

Study Design

This study is a randomized, double-blind, placebo-controlled clinicaltrial of 4-week duration in which a total of 100 individuals withatherosclerosis will be enrolled, randomized, and treated as follows:

The experimental group receives4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoicacid, potassium salt (300 mg/day). The control group will receiveatorvastatin (80-mg daily).

Main Criteria for Inclusion

Male and female individuals

Between 30-75 years of age

At least one obstruction in a major cardiac vessel with at least a 20%luminal diameter narrowing by visual estimation.

A “target vessel” for IVUS interrogation with no more than 50% luminalnarrowing throughout a segment that was a minimum of 30 mm in length(the “target segment”). The target vessel must not have undergoneprevious intervention, nor have been a candidate for intervention at thetime of Baseline catheterization.

Low-density lipoprotein cholesterol (LDL-C) between 125 and 210 mg/dLfollowing a 4- to 10-week washout period if the individual is takingantihyperlipidemic medication.

Uric acid levels in the blood exceed 360 μmol/L (6 mg/dL) for a femaleindividual or 400 μmol/L (6.8 mg/dL) for a male individual; or uric acidlevels in urine exceed 800 mg/day (in a male individual) and greaterthan 750 mg/day (in a female individual).

Endpoints

The primary efficacy parameter is restoration of uric acid levels tomedically-acceptable levels.

The secondary endpoints are:

a. Change in TPV

b. Change in percent plaque PPV

Example 39

2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid was administered to 12 healthy subjects as follows:

a. 100 mg, fasted state (4 subjects)

b. 100 mg, fed state (4 subjects)

c. 200 mg, fasted state (4 subjects)

Each group showed signs of uric acid lowering effects, as shown in FIG.6

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested toindividuals skilled in the art are to be included within the spirit andpurview of this application and scope of the appended claims.

1. A compound of formula (III), or a metabolite, pharmaceuticallyacceptable salt, solvate, ester, tautomer or prodrug thereof:

wherein X is CH or N; W is O, S, S(O), S(O)₂, NH, N (optionallysubstituted alkyl), NC(O) (optionally substituted alkyl) or CH₂; R¹ isH, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F; R³ andR^(3′) are independently selected from H and lower alkyl, or R³ andR^(3′) together with the carbon to which they are attached form a 4-,5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O; R² is selected from the group consisting of(a), (b), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond; Qand Q′ are independently selected from N and CH; R^(P) is methyl, ethyl,propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcyclopropylmethyl; R⁸, R⁹ and R¹⁰ are independently selected from H, F,Cl, Br, CH₃, CF₃, CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH,OCF₃, NH₂ and NHCH₃; R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl,cyclopropyl, tert-butyl, cyclobutyl or methyl; and R¹², R¹³, R¹⁴ and R¹⁵are independently H or methyl.
 2. The compound of claim 1, wherein: X isN.
 3. The compound of claim 1, wherein: W is S or O.
 4. The compound ofclaim 1, wherein: R² is (a)


5. The compound of claim 4, wherein:

represents a carbon-carbon double bond; and R^(P) is cyclopropyl.
 6. Thecompound of claim 1, wherein: X is N; W is S; and R¹ is Cl, Br, I,optionally substituted methyl, CF₃, CHF₂ or CH₂F.
 7. The compound ofclaim 1, wherein: R³ and R^(3′) are not H.
 8. The compound of claim 1,wherein: R³ and R^(3′) are H.
 9. The compound of claim 1, wherein: R³and R^(3′) together with the carbon to which they are attached form a4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O.
 10. The compound of claim 1, wherein: R³ andR^(3′) together with the carbon to which they are attached form a 4-,5-, or 6-membered ring.
 11. A compound of formula (II), wherein thecompound of formula (II) is a3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazolewherein the substituent at the 3-position is —R^(B), or pharmaceuticallyacceptable salt, solvate, or tautomer thereof: wherein, R^(B) is—SCH₂C(═O)R^(1a), SCH₂-tetrazolyl, —SCH₂C(═O)NHOH,—SCH₂C(═O)O-alkyl-OC(═O)R^(3a), —SCH₂C(═O)O-alkyl-OC(═O)OR^(3a),—SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b), or —SCH₂C(Oalkyl)₃; R^(1a) isOR^(2a), SR^(3a), NR^(4a)R^(4b), at least one amino acid, a peptide, alipid, a phospholipid, a glycoside, a nucleoside, a nucleotide,oligonucleotide, polyethylene glycol, or a combination thereof, whereinR^(2a) is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl oroptionally substituted heteroaryl; or R^(2a) is a pharmaceuticallyacceptable cation; or R^(2a) is [C(R^(5a))(R^(5b))]_(m)R^(5c); R^(3a) ishydrogen, optionally substituted C₁-C₁₀ alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl; or R^(3a) is [C(R^(5a))(R^(5b))]_(n)R^(5c); R^(4a) ishydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; and R^(4b) is hydrogen, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted cycloalkyl oroptionally substituted heterocycloalkyl; or R^(4b) is[C(R^(5a))(R^(5b))]_(n)R^(5c), wherein each R^(5a) is independentlyhydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, alipid, a phospholipid, a glycoside, a nucleoside, a nucleotide,oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted-L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionallysubstituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl,optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted-L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl,optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted-L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionallysubstituted -L-C₁-C₄ alkylamine, optionally substituted-L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl,optionally substituted -L-C₅-C₇ heteroaryl,

each R^(5b) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^(5c) is hydrogen, halogen, cyano, nitro, at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl,optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionallysubstituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionallysubstituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂; y₁ is 0, 1, 2 or 3; Y isOH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂,OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein Y² and Y³ are eachindependently hydrogen or methyl; or Y² and Y³ are taken together withthe nitrogen to which they are attached to form a five or six memberedring that optionally contains an oxygen atom or a second nitrogen atom;and Y⁴ is an electron pair or an oxygen atom; m is 1, 2, 3, 4; n is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and wherein if R^(2a) is-[C(R^(5a))(R^(5b))]_(m)R^(5c) then at least one of R^(5a), R^(5b) andR^(5c) is not hydrogen. 12-23. (canceled)
 24. The compound of claim 11,wherein: R^(1a) is OR^(2a).
 25. (canceled)
 26. The compound of claim 24,wherein: R^(2a) is a pharmaceutically acceptable cation.
 27. Thecompound of claim 24, wherein: R^(2a) is a pharmaceutically acceptablecation selected from L⁺, Na⁺ K⁺, Mg⁺⁺, Ca⁺⁺ or a protonated amine.28-67. (canceled)
 68. A pharmaceutical composition comprising: (i) acompound of formula (I); or (ii) a compound of formula (II), wherein thecompound of formula (II) is a3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazolewherein the substituent at the 3-position is —R^(B); or (iii) a compoundof formula (III); or (iv) a combination thereof;

wherein X is CH or N; W is O, S, S(O), S(O)₂, NH, N (optionallysubstituted alkyl), NC(O) (optionally substituted alkyl) or CH₂; R¹ isH, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F; R³ andR^(3′) are independently selected from H and lower alkyl, or R³ andR^(3′) together with the carbon to which they are attached form a 4-,5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O; R² is selected from the group consisting of(a), (b), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond; Qand Q′ are independently selected from N and CH; R^(P) is methyl, ethyl,propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcyclopropylmethyl; R⁸, R⁹ and R¹⁰ are independently selected from H, F,Cl, Br, CH₃, CF₃, CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH,OCF₃, NH₂ and NHCH₃; R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl,cyclopropyl, tert-butyl, cyclobutyl or methyl; and R¹², R¹³, R¹⁴ and R¹⁵are independently H or methyl; R^(B) is —SCH₂C(═O)R^(1a),—CH₂-tetrazolyl, —SCH₂C(═O)NHOH, —SCH₂C(═O)O-alkyl-OC(═O)R^(3a),—SCH₂C(═O)O-alkyl-OC(═O)OR^(3a), —SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b),or —SCH₂C(Oalkyl)₃; R^(1a) is OR^(2a), SR^(3a), NR^(4a)R^(4b), at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or acombination thereof, wherein R^(2a) is substituted C₁-C₄ alkyl,optionally substituted C₅-C₁₀ alkyl, optionally substituted heteroalkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl or optionally substitutedheteroaryl; or R^(2a) is a pharmaceutically acceptable cation; or R^(2a)is [C(R^(5a))(R^(5b))]_(m)R^(5c); R^(3a) is hydrogen, optionallysubstituted C₁-C₁₀ alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl; orR^(3a) is [C(R^(5a))(R^(5b))]_(n)R^(5c); R^(4a) is hydrogen, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl or optionally substituted heterocycloalkyl; andR^(4b) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; or R^(4b) is —[C(R^(5a))(R^(5b))]_(n)R^(5c), whereineach R^(5a) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^(5b) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^(5c) is hydrogen, halogen, cyano, nitro, at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl,optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionallysubstituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionallysubstituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂; y₁ is 0, 1, 2 or 3; Y isOH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂,OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein Y² and Y³ are eachindependently hydrogen or methyl; or Y² and Y³ are taken together withthe nitrogen to which they are attached to form a five or six memberedring that optionally contains an oxygen atom or a second nitrogen atom;and Y⁴ is an electron pair or an oxygen atom; m is 1, 2, 3, 4; n is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and wherein if R^(2a) is[C(R^(5a))(R^(5b))]_(m)R^(5c) then at least one of R^(5a), R^(5b) andR^(5c) is not hydrogen; R⁴ is H, lower alkyl, lower alkenyl or loweralkynyl; R⁵, R^(5′), R⁶, R^(6′) and R⁷ are independently selected fromH, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl,substituted ethyl, substituted n-propyl, substituted i-propyl,cyclopropyl, cyclobutyl, cyclopentyl, CF₃, CHF₂, CH₂F, NH₂, NHR′, NR′R″,OR′, SR′, C(O)R′, CO₂H, a salt of CO₂H, COOR′, CONH₂, CONHR′, CONR′R″,SO₃H, a salt of SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl ora heterocycle, wherein R′ is H, C₁₋₃ alkyl, substituted C₁₋₃ alkylwherein said substituents are selected from CF₃, OH, OC₁₋₃ alkyl, COC₁₋₃alkyl, COOH, COOC₁₋₃ alkyl, NH₂, NHC₁₋₃ alkyl, N(C₁₋₃ alkyl)(C₁₋₃alkyl), CONHC₁₋₃ alkyl, aryl or a heterocycle; R″ is H, C₁₋₃ alkyl,substituted C₁₋₃ alkyl wherein said substituents are selected from CF₃,OH, OC₁₋₃ alkyl, COC₁₋₃ alkyl, COOH, COOC₁₋₃ alkyl, NH₂, NHC₁₋₃ alkyl,N(C₁₋₃ alkyl)₂, CONHC₁₋₃ alkyl, aryl or a heterocycle; or R′ and R″together with the nitrogen atom to which they are attached form a 4-,5-, or 6-membered heterocyclic ring; or a metabolite, pharmaceuticallyacceptable salt, solvate, ester, tautomer or prodrug thereof; and (v)optionally one or more pharmaceutically acceptable carriers.
 69. Thecomposition of claim 68, further comprising a second agent effective forthe treatment of the gout.
 70. The composition of claim 69, wherein thesecond agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, axanthine dehydrogenase, a xanthine oxidoreductase inhibitor, orcombinations thereof.
 71. The composition of claim 69, wherein thesecond agent is allopurinol, febuxostat, FYX-051, or combinationsthereof.
 72. A method of reducing serum uric acid levels in anindividual, comprising administering; (i) a compound of formula (I); or(ii) a compound of formula (II), wherein the compound of formula (II) isa3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazolewherein the substituent at the 3-position is —R^(B); or (iii) a compoundof formula (III); or (iv) a combination thereof;

wherein X is CH or N; W is O, S, S(O), S(O)₂, NH, N (optionallysubstituted alkyl), NC(O) (optionally substituted alkyl) or CH₂; R¹ isH, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedn-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F; R³ andR^(3′) are independently selected from H and lower alkyl, or R³ andR^(3′) together with the carbon to which they are attached form a 4-,5-, or 6-membered ring, optionally containing 1 or 2 heteroatomsselected from N, S and O; R² is selected from the group consisting of(a), (bi), (c) and (d):

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond; Qand Q′ are independently selected from N and CH; R^(P) is methyl, ethyl,propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcyclopropylmethyl; R⁸, R⁹ and R¹⁰ are independently selected from H, F,Cl, Br, CH₃, CF₃, CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH,OCF₃, NH₂ and NHCH₃; R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl,cyclopropyl, tert-butyl, cyclobutyl or methyl; and R¹², R¹³, R¹⁴ and R¹⁵are independently H or methyl; R^(B) is —SCH₂C(═O)R^(1a),—SCH₂-tetrazolyl, —SCH₂C(═O)NHOH, —SCH₂C(═O)O-alkyl-OC(═O)R^(3a),—SCH₂C(═O)O-alkyl-OC(═O)OR^(3a), —SCH₂C(═O)O-alkyl-OC(═O)NR^(4a)R^(4b),or —SCH₂C(Oalkyl)₃; R^(1a) is OR^(2a), SR^(3a), NR^(4a)R^(4b), at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or acombination thereof, wherein R^(2a) is substituted C₁-C₄ alkyl,optionally substituted C₅-C₁₀ alkyl, optionally substituted heteroalkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl or optionally substitutedheteroaryl; or R^(2a) is a pharmaceutically acceptable cation; or R^(1a)is [C(R^(5a))(R^(5b))]_(m)R^(5c); R^(3a) is hydrogen, optionallysubstituted C₁-C₁₀ alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl; orR^(3a) is [C(R^(5a))(R^(5b))]_(n)R^(5c); R^(4a) is hydrogen, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted cycloalkyl or optionally substituted heterocycloalkyl; andR^(4b) is hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl; or R^(4b) is [C(R^(5a))(R^(5b))]_(n)R^(5c), whereineach R^(5a) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^(5b) is independently hydrogen, halogen, cyano, nitro, at leastone amino acid, a peptide, a lipid, a phospholipid, a glycoside, anucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH,-L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted-L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionallysubstituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl,optionally substituted -L-C₃-C₇ cycloalkyl, optionally substitutedL-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionallysubstituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^(5c) is hydrogen, halogen, cyano, nitro, at least one amino acid, apeptide, a lipid, a phospholipid, a glycoside, a nucleoside, anucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl,optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionallysubstituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted-L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionallysubstituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂; y₁ is 0, 1, 2 or 3; Y isOH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂,OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein Y² and Y³ are eachindependently hydrogen or methyl; or Y² and Y³ are taken together withthe nitrogen to which they are attached to form a five or six memberedring that optionally contains an oxygen atom or a second nitrogen atom;and Y⁴ is an electron pair or an oxygen atom; m is 1, 2, 3, 4; n is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and wherein if R^(2a) is-[C(R^(5a))(R^(5b))]_(m)R^(5c) then at least one of R^(5a), R^(5b) andR^(5c) is not hydrogen; R⁴ is H, lower alkyl, lower alkenyl or loweralkynyl; R⁵, R^(5′), R⁶, R^(6′) and R⁷ are independently selected fromH, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl,substituted ethyl, substituted n-propyl, substituted i-propyl,cyclopropyl, cyclobutyl, cyclopentyl, CF₃, CHF₂, CH₂F, NH₂, NHR′, NR′R″,OR′, SR′, C(O)R′, CO₂H, a salt of CO₂H, COOR′, CONH₂, CONHR′, CONR′R″,SO₃H, a salt of SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl ora heterocycle, wherein R′ is H, C₁₋₃ alkyl substituted C₁₋₃ alkylwherein said substituents are selected from CF₃, OH, OC₁₋₃ alkyl, COC₁₋₃alkyl, COOH, COOC₁₋₃ alkyl, NH₂, NHC₁₋₃ alkyl, N(C₁₋₃ alkyl)(C₁₋₃alkyl), CONHC₁₋₃ alkyl, aryl or a heterocycle; R″ is H, C₁₋₃ alkylsubstituted C₁₋₃ alkyl wherein said substituents are selected from CF₃,OH, OC₁₋₃ alkyl, COC₁₋₃ alkyl, COOH, COOC₁₋₃ alkyl, NH₂, NHC₁₋₃ alkyl,N(C₁₋₃ alkyl)₂, CONHC₁₋₃ alkyl, aryl or a heterocycle; or R′ and R″together with the nitrogen atom to which they are attached form a 4-,5-, or 6-membered heterocyclic ring; or a metabolite, pharmaceuticallyacceptable salt, solvate, ester, tautomer or prodrug thereof.
 73. Thecompound of claim 1, which is a pharmaceutically acceptable salt of acompound of formula (III).
 74. The compound of claim 73, wherein thepharmaceutically acceptable salt is a L⁺, Na⁺, K⁺, Mg⁺⁺, Ca⁺⁺ or aprotonated amine salt.
 75. The pharmaceutical composition of claim 68,comprising: ii) a compound of formula (II); or a metabolite,pharmaceutically acceptable salt, solvate, ester, tautomer or prodrugthereof; and v) optionally one or more pharmaceutically acceptablecarriers.
 76. The pharmaceutical composition of claim 75, comprising:ii) a pharmaceutically acceptable salt of a compound of formula (II); v)optionally one or more pharmaceutically acceptable carriers.
 77. Thepharmaceutical composition of claim 73, wherein: R^(B) isSCH₂C(═O)R^(1a); R^(1a) is OR^(2a) and; R^(2a) is a pharmaceuticallyacceptable cation.